Plasticity and cross-talk of Interleukin 6-type cytokines

Cytokine & Growth Factor Reviews 23 (2012) 85–97

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Plasticity and cross-talk of Interleukin 6-type cytokines Christoph Garbers a, Heike M. Hermanns b, Fred Schaper c, Gerhard Mu¨ller-Newen d, Joachim Gro¨tzinger e, Stefan Rose-John e, Ju¨rgen Scheller a,* a

Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Du¨sseldorf, Germany Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Wu¨rzburg, Wu¨rzburg, Germany c Institute of Biology, Otto-von-Guericke-University, Magdeburg, Germany d Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany e Institute of Biochemistry, Christian-Albrechts-University, Olshausenstrabe 40, Kiel, Germany b

A R T I C L E I N F O

A B S T R A C T

Article history: Available online 15 May 2012

Interleukin (IL)-6-type cytokines are critically involved in health and disease. The duration and strength of IL-6-type cytokine-mediated signaling is tightly regulated to avoid overshooting activities. Here, molecular mechanisms of inter-familiar cytokine cross-talk are reviewed which regulate dynamics and strength of IL-6 signal transduction. Both plasticity and cytokine cross-talk are significantly involved in pro- and anti-inflammatory/regenerative properties of IL-6-type cytokines. Furthermore, we focus on IL6-type cytokine/cytokine receptor plasticity and cross-talk exemplified by the recently identified composite cytokines IL-30/IL-6R and IL-35, the first inter-familiar IL-6/IL-12 family member. The complete understanding of the intra- and extracellular cytokine networks will aid to develop novel tailormade therapeutic strategies with reduced side effects. ß 2012 Elsevier Ltd. All rights reserved.

Keywords: Interleukin-6 Cross-talk Plasticity Signal transduction

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IL-6-type cytokines, their receptors and main signaling pathways . . . . . . . . . . . . . . . . . . . . . . Plasticity and intra-familiar cross-talk of IL-6-type cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . IL-35: the first shared IL-6/IL-12 family cytokine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inter-familiar cross-talk of the major early pro-inflammatory cytokines IL-6, IL-1 and TNFa. Inter-familiar cross-talk between IL-6 and glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inter-familiar cross-talk of IL-6 and G-protein-coupled receptors. . . . . . . . . . . . . . . . . . . . . . . Inter-familiar cross-talk of IL-6 and receptor tyrosine kinase signaling: taming insulin . . . . . Conclusions and future directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Cytokines are released by a huge variety of different cell types and generally act locally as auto- and paracrine factors. Their functions are involved in multiple physiological processes, including differentiation, proliferation, migration and apoptosis of their target cells [1–4]. Therefore, their ability to signal and activate other cells must be tightly regulated, since uncoordinated

* Corresponding author. Tel.: +49 211 8112724; fax: +49 211 8112726. E-mail address: [email protected] (J. Scheller). 1359-6101/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cytogfr.2012.04.001

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cytokine signaling correlates with several pathophysiological states, including acute and chronic inflammatory diseases, neoplastic disorders, cancer and autoimmune diseases [5]. In a simplistic view, any cytokine binds to a unique cytokine receptor pair, leading to the activation of intracellular signaling pathways on target cells. Receptor proteins and major signaling pathways of IL-6-type cytokines have been investigated over the last two decades (reviewed in [6,7]). Most data have been generated under controlled experimental conditions using defined cell lines stimulated with single cytokines. This reductionistic experimental approach was extremely successful to identify the basic signaling pathways, but when combined,

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cytokines, hormones and other stimuli might have additive, synergistic or antagonistic effects, a phenomenon referred to as cross-talk. In vivo, cross-talk is more likely the rule but the exception, since each cell has constantly to react to a variety of factors at almost the same time. In line with this, the reductionistic experimental approach was recently challenged by several studies dealing with cytokine cross-talk. Importantly, it was found that cytokine cross-talk does not only exist at the level of interfering signal transduction pathways but also at the level of cytokines and their receptors. Here, plasticity within cytokine/ cytokine receptor binding sites allows, to a certain extent, that a cytokine can use different receptor combinations. Very little is known about how a cytokine discriminates between different options, but we feel that this decision will be driven by affinity and receptor abundance. In this review, we focus on intra- and interfamiliar IL-6-type cytokine cross-talk. Intra-familiar IL-6-type cytokine cross-talk was described for several cytokines of the IL-6-type family and is based on binding site/interface plasticity of the cytokine to its receptor(s). Inter-familiar IL-6-type cross-talk was recently highlighted by studies elucidating the connection between IL-6 and IL-1 signaling pathways. Sections discussing the current knowledge of IL-6-type cytokine cross-talk are preceded by an introduction to IL-6-type cytokines, their basic receptor composition and major signaling pathways. We hope that this review leads to a better perception of the emerging world of cytokine/cytokine receptor cross-talk and plasticity not only within the IL-6-type family of cytokines.

2. IL-6-type cytokines, their receptors and main signaling pathways All cytokines of the IL-6 family belong to the four-helical bundle cytokine family. These proteins share little sequence homology and were only recognized to be related by prediction and analysis of their protein fold [8]. Interestingly, the four-helical bundle fold with an up–up–down–down topology has so far only been found in mediator proteins such as interleukins, cytokines and growth factors [9]. Cytokines signal through a specific combination of b-receptors with supporting a-receptors to increase target cell specificity and to prevent unwanted cellular activation. Cytokine receptors for cytokines of the IL-6 family belong to the immunoglobulin superfamily [8,9]. Two different types of cytokine receptors are distinguished. Short chain a-receptors consisting of 3 immunoglobulin-/fibronectin-like domains bind their cognate ligands and present these to long chain b-receptors consisting of 5–8 immunoglobulin (Ig)-like/fibronectin-like domains. These long chain b-receptors form homo- or heterodimers and initiate intracellular signaling [10]. All cytokines of the IL-6 family signal via the long chain signal transducing b-receptor glycoprotein 130 kDa (gp130). As shown in Fig. 1A, IL-6 and IL-11 use a homodimer of gp130 whereas all other members of the IL-6 family use heterodimers of gp130 and one of the other b-receptors leukemia inhibitory factor receptor (LIFR), oncostatin M receptor (OSMR) or WSX-1 (IL-27R). A somewhat special case is the cytokine IL-31, which binds to a heterodimer of OSMR and the IL31 receptor A (IL-31RA) also known as gp130-like protein (GPL) [11]. Some cytokines need additional non-signaling a-receptors to bind to their b-receptors (Fig. 1A). These a-receptors are either membrane-bound such as IL-6R for IL-6, IL-11R for IL-11 and ciliary neurotrophic factor receptor (CNTFR) for CNTF or cardiotrophinlike cytokine (CLC), or are soluble such as Epstein-Barr virus induced gene 3 (EBI3) for IL-30 (p28) to form the composite cytokine IL-27 [12]. The cytokines OSM, LIF and IL-31 do not need

an additional a-receptor. It is still not clear if cardiotrophin-1 (CT1) needs an a-receptor [13] (Fig. 1A). Except for IL-31, all IL-6-type cytokines bind to the b-receptor gp130, indicating a high degree of binding site plasticity within gp130 and the respective cytokines. Crystal structures of the cytokine/receptor complex have been solved for IL-6 in complex with IL-6R and gp130 and for the CBM of gp130 in complex to LIF [14,15] (Fig. 1B). Binding of IL-6-type cytokines is mainly mediated by ionic and hydrophobic interactions [16], however, inspection of the electrostatic surface potential of site II of IL-6, CNTF, LIF and OSM (constituted by helices A and C) and the cytokine binding module (CBM) of gp130 (domains 2 and 3) reveals almost no similarity (Fig. 1B). Per definition, site II and site III are binding sites within the cytokine which interact with the b-receptors, whereas site I is the binding site for the a-receptor (Fig. 1C and D). Therefore, the interaction between site II of the respective cytokine and the CBM of gp130 has been described as a chemical plasticity resulting in a slightly different orientation of the cytokine and the CBM of gp130 [17]. Gp130 is expressed on all cells whereas the other receptor subunits show a more restricted expression profile [5]. Since no cytokine of the IL-6 family can signal via gp130 alone, it follows that the expression of the additional a- and b-receptor subunits determines whether a given cell will be responsive to the cytokine [5]. This is illustrated by the two cytokines IL-6 and IL-11, both signaling through a homodimer of gp130 plus additional specific a-receptors (Fig. 1A). In this case, expression of the a-receptors IL6R and IL-11R determines responsiveness of a target cell. The IL-6R is mainly expressed on hepatocytes and some leukocyte populations, including macrophages, monocytes, neutrophils, B- and Tcells [18], whereas the IL-11R has been detected on lymphocytes, B-cells, macrophages, endothelial cells, hematopoietic cells and osteoclasts [19]. These data, however, did not include quantitative analysis of a-receptor expression, and it is not possible to predict, if a cell, expressing both a-receptors, reacts more efficiently to IL-6 or IL-11. Moreover, comprehensive data covering all receptors and cell types are still missing, and it is so far unclear whether cells can adapt their receptor expression profile, for example during pathophysiologic conditions. Examples of activation-dependent receptor presentation were shown for CD4 T cells, which lose membrane-bound IL-6R during activation via a process called ectodomain shedding mediated by ADAM proteases [20,21] and for hepatic cells or fibroblasts, which internalize gp130 rapidly in response to IL-1b [22]. In case of IL-6, an additional mechanism for cellular activation has been recognized. Besides the membrane-bound IL-6R, a soluble form of the IL-6R (sIL-6R) is present in many body fluids. The sIL-6R is generated by limited proteolysis by ADAM10 or ADAM17 of the membrane-bound IL-6R and to a lesser extent by translation from an alternatively spliced mRNA in which the exon coding for the transmembrane region has been skipped [18]. The sIL-6R can still bind its ligand IL-6 and the complex of IL-6 and sIL6R interacts with gp130 and thus activates cells which do not express IL-6R and are therefore unresponsive to IL-6 alone. This signaling paradigm has been called IL-6 trans-signaling [23], whereas signaling via the membrane-bound IL-6R is referred to as classic signaling [18] (Fig. 1A). The complex of IL-6 and sIL-6R can stimulate all cells of the body and thereby mimic signals from other cytokines of the IL-6 family [5]. Interestingly, IL-6 transsignaling is mimicked by the viral ortholog of IL-6 (vIL-6) encoded by the human herpes virus 8 (HHV8), which directly binds to and stimulates gp130 and does not depend on IL-6R [24,25]. In principle, the soluble forms of the other two membrane-bound areceptors CNTFR and IL-11R can also form biologically active soluble complexes, CNTF/sCNTFR [26] and IL-11/sIL-11R [27]. It is, however, unlikely that trans-signaling of CNTF and IL-11 via

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Fig. 1. Receptor complexes and major JAK/STAT signaling pathways of the IL-6-type family of cytokines. (A) All cytokines of the gp130-signaling family use gp130 (red) as at least one part of the signal-transducing b-receptor complex. Some cytokines need additional b-receptor molecules directly involved in signal transduction into the cell (LIF-R (dark orange), OSM-R (orange), WSX-1 (wheat), GPL (dark red) or non-signaling a-receptors (IL-6R (blue), IL-11-R (green), CNTF-R (dark grey), EBI3 (grey)). Cytokines of this family are IL-6 (dark blue), IL-11 (green), CNTF (black), CLC (black), CT-1 (grey), OSM (grey), LIF (grey), IL-27 (light grey) and IL-31 (lightest grey). CLC may require an additional a-receptor. The dominant STAT factor activations are marked in bold, however, this general assignment might not be true for all cells. (B) Comparison of the binding site II of IL-6-type cytokines IL-6, CNTF, LIF and OSM (yellow circle) and the complex of IL-6 (site II) with gp130 (cytokine binding module (CBM) domains 2–3, yellow circle). (C) Structure of IL-6. The binding sites of IL-6 to the IL-6R (site I) and to gp130 (site II and site III) are indicated. (D) Schematic assembly of the hexameric gp130signaling complex. Sites I, II and III of IL-6 are indicated with I, II, III. Site I is in contact with IL-6R, site II with gp130-CBM and site III with gp130-Ig (D1).

sCNTFR and sIL-11R is relevant in vivo, since no naturally occurring sCNTFR and sIL-11R were found so far. On the other hand, IL-30 signals as composite cytokine IL-27 only via the trans-signaling mechanism, since EBI3 is only expressed as a soluble protein. It was shown that a soluble form of gp130 (sgp130) is the natural inhibitor of IL-6 trans-signaling [28,29]. Therefore, recombinant sgp130 is used as a molecular tool to distinguish between classic- and trans-signaling. IL-6 is known to exhibit proinflammatory and regenerative activities [30]. For example, IL-6/  mice are more susceptible in an inflammatory bowel disease model as compared to wild type mice [31] but protected in mouse models of rheumatoid arthritis [32,33]. It turned out that for proinflammatory signals, IL-6 acts via the sIL-6R whereas the regenerative activities of IL-6 and the induction of the hepatic acute-phase response are induced via the membrane-bound IL-6R [30]. This has led to the evaluation of an Fc-fusion protein of sgp130 (sgp130Fc) as a therapeutic principle to neutralize the

pro-inflammatory activities of IL-6, which would not compromise other beneficial activities of IL-6 [34,35]. Importantly, sgp130Fc does not inhibit the signaling of the other IL-6-type cytokines [36]. First clinical trials with the sgp130Fc protein are planned for 2012. Despite a molar excess of sIL-6R over IL-6, free IL-6 and IL-6 in IL-6/ sIL-6R complexes are present which allows both classic and transsignaling. Under these conditions, sgp130 was, however, able to trap all free IL-6 molecules in IL-6/sIL-6R/sgp130 complexes, resulting in inhibition of classic signaling by sgp130 [37]. Finally, binding of IL-6-type cytokines to signal-transducing transmembrane b-receptors induces the activation of receptorbound Janus kinases (JAKs) and subsequent signaling pathways including signal transducers and activators of transcription (STAT) transcription factors, mitogen-activated protein kinases (MAPK), in particular the extracellular signal regulated kinases (Erk1/2), and phosphoinositide 3-kinase (PI3K). Several control mechanisms and negative feedback regulators are limiting IL-6 signaling

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pathways at different levels, including receptor internalization, expression of suppressors of cytokine signaling proteins (SOCS), the action of protein inhibitors of activated STATs (PIAS) and protein tyrosine phosphatases (PTP). For a detailed description of intracellular signaling of IL-6-type cytokines, we recommend the review article by Heinrich et al. [6]. 3. Plasticity and intra-familiar cross-talk of IL-6-type cytokines The well-documented plasticity of gp130 as common b-chain receptor of IL-6-type cytokines is not the only example of receptor cross-talk within the IL-6 family. OSM can signal via two different pairs of b-receptors, namely LIFR/gp130 (type I) and OSMR/gp130 (type II) [6], which broadens the spectrum of cells that can be activated by OSM. This feature seems to be restricted to human OSM, since in mice, OSM exhibits only high affinity for the heterodimeric receptor pair OSMR/gp130 [38,39]. Interestingly, ongoing studies indicate that rat OSM resembles human OSM in signaling via both type I and type II receptor complexes (own unpublished results, H.M.H.). Plasticity is not restricted to cytokine/b-chain receptor interaction. The IL-6R can also interact with different ligands. Besides IL-6 [30], the IL-6R was shown to bind to CNTF, albeit at lower affinity compared to CNTF/CNTFR interaction. The CNTF/IL-6R complex was able to induce the formation of a heterodimer of gp130/LIFR for the activation of signal transduction [40] (Fig. 2). Another ligand for the IL-6R was recently shown to be IL-30, the IL27 cytokine subunit p28 [41] (Fig. 2). The binding of IL-30 to IL-6R plus assembly of the b-receptor signaling complex leads to activation and phosphorylation of STAT1 and STAT3. Like in the case of CLC, the cytokine-like factor-1 (CLF) was needed for efficient secretion of IL-30, but not for signaling. During formation of the breceptor signaling complex, CLF is replaced by one of the breceptors. CLF interacts with site III of the cytokines CLC and IL-30. In the case of CLC, CLF is replaced by the LIFR upon formation of the signaling competent ternary receptor complex [42]. For IL-30, the common architecture of the cytokine/b-receptor complex is not possible in which site II interacts with CBM of gp130 and site III the Ig-like domain of LIFR or OSMR or a second gp130 in case of gp130 homodimer formation. As a consequence, IL-27 (IL-30/EBI3) interacts with gp130 via site III and with WSX-1 via site II. Therefore, in the case of IL-30/CLF, CLF must be replaced by gp130 during b-receptor complex formation. The receptor composition of IL-30/IL-6R has not been identified [41]. The proposed gp130/WSX1 heterodimer seemed to be likely, but was recently challenged [43]. The authors demonstrate that the beneficial effects of IL-30 in the treatment of liver injury also occur in WSX-1-deficient mice, making the signaling via a gp130/WSX-1 heterodimer impossible. Therefore, the signal-transducing b-receptors for IL-30/IL-6R remains to be CNTF

determined (Fig. 2). In IL-6 trans-signaling, IL-6 can induce signaling via the soluble IL-6R [23,44]. Interestingly, CNTF can also form a biologically active complex with sIL-6R but a naturally occurring sCNTFR was not described so far (Fig. 2) [40]. It remains to be shown, whether IL-30 is also able to form a biologically active composite cytokine with the sIL-6R (Fig. 2). This is of importance, since in humans about 30–50 ng/ml sIL-6R are present in the circulation. In pathophysiological conditions sIL-6R levels rise 2–3fold. Whether the biological activity of CNTF/sIL-6R and IL-30/sIL-6R complexes would be inhibited by sgp130 was not investigated. Since gp130 shows a remarkable plasticity by integrating the binding of all IL-6-type cytokines to a single b-receptor, specific differences between the signal transduction of IL-6-type cytokines must be determined not only by receptor expression pattern but also by the accompanying second b-receptor chain. However, since some cytokines use the same homo- or heterodimeric receptor complexes such as IL-6 and IL-11 or LIF, CNTF, OSM, CLC and CT-1, it is still not clear whether the intracellular signaling of these cytokines is identical or if the signal transduction of the same breceptor complex is different with respect to the cytokine bound. Moreover, it has to be stated that, although the described cross-talk of cytokines and cytokine receptors leads to multiple possible combination of active b-receptor complexes, cytokine binding mainly results in the activation of only a few major signaling pathways, which include the aforementioned STAT, MAPK and PI3K proteins. It is not clear how this is regulated in space and time for dynamic signal transduction. Even though the plasticity of cytokine/cytokine receptor interactions is the basis for the broad IL-6-type cytokine redundancy, differences in their signal transduction should be expected and were indeed demonstrated [45]. 4. IL-35: the first shared IL-6/IL-12 family cytokine The latest discovered cytokine of the IL-6 family is a heterodimer composed of p35 (cytokine subunit of IL-12) and EBI3 (a-receptor subunit of IL-27). IL-35 was discovered by Collison et al. [46], although the ability of the two proteins to form a complex and to be secreted together from cells was already demonstrated ten years before [47]. IL-35 bridges the IL-6 and the IL-12 cytokine families. The IL-12 family consists of the two heterodimers IL-12 (p35/p40; cytokine/a-receptor) [48] and IL-23 (p19/p40) [49]. IL-35 it is the first shared member of the two cytokine families and defines an inter-familiar cross-talk (Fig. 3). The recently identified b-receptors and the specific STAT proteins activated by IL-35 are unconventional [50]. IL-35 signals via three different pairs of b-receptors, a gp130 homodimer, an IL-12Rb2 homodimer or a gp130/IL-12Rb2 heterodimer. Whereas IL-35-induced gp130 homodimer formation leads to IL-30 (p28) ?

CNTFR gp130/LIFR

High affinity

IL 6R IL-6R gp130/LIFR

sIL 6R sIL-6R gp130/LIFR

Low affinity

EBI3 gp130/WSX-1

High affinity

IL 6R IL-6R gp130/?

sIL 6R sIL-6R gp130/?

Low affinity

Fig. 2. Plasticity and intra-familiar cross-talk of CNTF and IL-30. CNTF binds to CNTFR (high affinity) and to membrane-bound and soluble IL-6R (low affinity). IL-30 binds to EBI3 (high affinity) and to membrane-bound IL-6R and very likely also to the soluble IL-6R. The receptor combination of IL-30/IL-6R might be the same as for IL-27 (IL-30/ EBI3).

C. Garbers et al. / Cytokine & Growth Factor Reviews 23 (2012) 85–97

IL-35

IL-27 IL-30 (p ) (p28

p35 ((IL-12A))

EBI3

89

IL-12 p35 (IL 12A) (IL-12A)

EBI3

gp130/WSX-1

gp130/gp130

gp130/IL-12Rβ2

IL-12Rβ2/IL-12Rβ2

STAT1/ STAT3/ STAT5

STAT1

STAT1/ STAT4

STAT4

p40

IL-12Rβ2/IL-12Rβ1 STAT1/ STAT3/ STAT4/ STAT5

Fig. 3. Receptor composition of the novel IL-6/IL-12 cytokine IL-35. IL-35 binds to and activates three different combinations of receptor complexes, a gp130 homodimer (STAT1), a gp130/IL-12Rb2 heterodimer (STAT1/STAT4) and an IL-12Rb2 homodimer (STAT4). For comparison the receptor composition of IL-27 and IL-12 plus main STAT factors is given.

the phosphorylation/activation of STAT1, the IL-12Rb2 homodimer phosphorylates only STAT4 and the gp130/IL-12Rb2 heterodimer phosphorylates both STAT1 and STAT4 leading to the formation of phosphorylated STAT1/STAT4 heterodimers (Fig. 3). Since IL-35 is composed of subunits from IL-12 and IL-27, it is not surprising that also the b-receptors are shared between the families, but the use of three different receptor pairings, resulting in the recruitment and activation of three different and distinct STAT proteins or STAT protein combinations, makes IL-35 a special family member. These findings furthermore underline the complex network of cytokine subunits and membrane-bound a- and b-receptors that are engaged in different combinations to induce biological actions. Since gp130 homodimer formation after IL-6 or IL-11 binding leads to the strong tyrosine phosphorylation of STAT3 and a weaker STAT1 activation, it is not trivial to imagine how the same gp130 homodimer after binding of IL-35 leads to STAT1 but not to STAT3 phosphorylation. Keeping this in mind, a comprehensive comparison of IL-35-, IL-6and IL-11-induced gp130 homodimer formation and signal transduction will help to unravel the basis of differential signal transduction from the same b-receptor complex depending on the bound cytokine. It can be speculated that binding of the different cytokines to the same receptor complex results in different orientations which might give access only to a specific set of tyrosine motifs in the intracellular region [51]. Extensive cross-talk and sharing of subunits and receptors makes it difficult to address the biological functions of the different cytokines in vivo. In the case of IL-35, neither EBI3-deficient nor p35-deficient mice represent solely IL-35-deficiency, because EBI3 is also involved in IL-27 signaling and p35 in IL-12 signaling. Therefore the reassignment of data achieved from these mice to the function of a single cytokine is impossible. One alternative strategy might be to compare p35- with p40-deficient mice. Both knock-out mice lack IL-12 signaling, but only p35-deficient mice additionally lack IL-35. Unfortunately, also interpretation of data from these animal experiments is complicated by cytokine subunit cross-talk, since p40 is shared between IL-12 [48] and IL-23 [49], making p40-deficient mice unresponsive to both cytokines. Finally, also the comparison of EBI3-deficient mice with IL-30-deficient mice is not helpful. Several reports have shown that IL-30 has functions independently of IL-27 [41,52,53], although the available data are conflicting. Shimozato et al. [53] reported that IL-30 alone can inhibit IL-27-mediated signaling, whereas Stumhofer et al. [52] identified IL-30 as a general antagonist of gp130-mediated signaling. In contrast, Crabe et al. [41] found that IL-30 is able to signal via the IL-6R. The latest report by Dibra et al. [43] underlines the agonistic signaling capacities of IL-30. They

characterize IL-30 as an anti-inflammatory cytokine capable of inhibiting inflammation-induced liver injury, an ability not executed by IL-27 (IL-30/EBI3). To date it is unclear how these different findings can be included into one model of IL-30 action, but it is clear that the listed IL-30 functions, which are independent of EBI3, are also absent in IL-30-deficient mice. This makes it impossible to dissect the role of IL-35 in vivo by comparing EBI3deficient with IL-30-deficient mice. In summary, it is currently not possible to generate conclusive IL-35-deficient mice and even data from the aforementioned knock-out animals of IL-30, EBI3, p40 have to be interpreted with caution due to intensive cytokine/cytokine receptor cross-talk. Presenting EBI3-deficient mice as IL-35-deficient mice [55] is misleading, since the in vivo roles of IL-35 cannot be dissected from IL-27. Time will tell whether sophisticated mouse-genetic approaches or the use of inhibitory antibodies, specifically targeting the EBI3:p35 heterodimer, will give rise to meaningful IL-35-deficient mice. Already in 1993, the shared IL-12/IL-23 subunit p40 has been shown to be able to inhibit signaling of IL-12 [56]. Later reports have proven the existence and antagonistic properties of an IL12p40 homodimer, named IL-12p80 [57,58]. This homodimer is able to bind to the IL-12Rb1, thereby antagonizing IL-12-mediated signaling by inhibiting binding of IL-12 to its receptor, without mediating biologic activities on its own [59]. In vivo, up to onethird of the total amount of p40 has been shown to exist as dimeric p80 [60]. IL-12p40 can also inhibit IL-23 mediated signaling, because IL-23 signals via a heterodimer of IL-12Rb1 and IL-23R. [61]. The inhibitory actions of p80 might also contribute to the phenotypes seen in p35 and p40-deficient mice, again complicating the generation of IL-35-deficient mice. Here, we have summarized cross-talk of the extracellular signaling network of cytokines, cytokine subunits and soluble receptors of the IL-6/IL-12 family. It is tempting to speculate that future work will unravel additional roles of single subunits, novel heterodimeric cytokines and agonistic or antagonistic functions of soluble cytokine receptors. Moreover, less attention was paid to the species specificity, since it is not clear whether the plasticity of cytokine receptor assembly within the IL-6/IL12 family is the same in men, rats or mice. This is exemplified by differences for human and murine OSM [38,39] and by rat CNTF which is able to engage signaling via a heterodimer of gp130/ LIFR in the absence of CNTFR [62], a feature that has not been observed for murine or human CNTF. Therefore, one has to be cautious with the transfer of findings from mice or rats to the human situation.

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5. Inter-familiar cross-talk of the major early pro-inflammatory cytokines IL-6, IL-1 and TNFa The duration and strength of IL-6-type cytokine-mediated signaling is tightly regulated to avoid overshooting pro-inflammatory activities. However, also anti-inflammatory activities have to be restricted since premature termination of the inflammatory response might prevent efficient anti-bacterial or regenerative activities. In the past decade much attention has been paid on the crosstalk elicited by the pro-inflammatory cytokines, IL-1b and TNFa with IL-6. Two important proteins were identified as critical regulators to influence IL-6-mediated signaling: the serine/ threonine protein kinase p38, a stress-activated MAPK, and the transcription factor NF-kB (Fig. 4). The liver is one of the most important organs responding to IL-6 [63]. IL-6 is crucial for the induction of hepatic class I and class II acute-phase gene expression and the regeneration of the liver after partial hepatectomy. These mechanisms are fundamental to cope with infections, toxic stress and traumata [64–66]. Already in the late 1980s it was recognized that IL-1b exerts a strong suppressive activity on the class II acute-phase protein release initiated by IL-6 [67]. This complex species- as well as tissue-specific suppressive activity depends on at least two activities of IL-1b. An immediately acting reduction/prevention of the IL-6-induced STAT3 tyrosine phosphorylation [22,68,69] and delayed effects influencing either the binding of STAT3 to promoters of target genes or the prolonged STAT3 activation [70–72]. The rapid inhibition of early STAT3 tyrosine phosphorylation was shown to be independent of protein de novo synthesis, the activity of tyrosine phosphatases and NF-kB activation; however, it required the activity of p38 MAPK [22,69].

Pro-inflammatory cytokines can directly impact on the cell surface expression of gp130. It has been shown that gp130 expression on human primary smooth muscle cells [73] and on mast cells [74] can be regulated by the IL-6/sIL-6R complex or by IL-10, respectively. Through pro-inflammatory cytokine mediated activation of the p38 MAPK target kinase MK2 (mitogen-activated protein kinase-activated kinase 2, also known as MAPKAPK2) serine residue 782 of gp130 becomes phosphorylated. Ser782 is located 4 amino acids N-terminally from the dileucine internalization motif [75]. Ser782-phosphorylation resulted in an accelerated endocytosis and lysosomal degradation of gp130 (Fig. 4). Thereby, the amplitude of IL-6-activated STAT3 was strongly reduced, resulting in diminished expression of a class II acutephase protein such as g-fibrinogen (FGG) [22]. Interestingly, two other highly related signaling receptors of the IL-6 family, LIFR and OSMR, were not susceptible to this kind of regulation. The internalization of gp130 might explain the earlier observation that the p38 MAPK-dependent rapid inhibition of STAT tyrosine phosphorylation is IL-6 specific and not observed for other STAT activating cytokines such as interferon (IFN-)g or IFNa [69]. Indeed, initial experiments indicate that cell surface localization of the IFNg receptor 1 (IFNGR1) is not affected by pro-inflammatory cytokines (own unpublished results, H.M.H.). SOCS3 is the most important feedback inhibitor of IL-6-type cytokine signaling [76]. Its negative regulatory effect relies on binding phosphorylated gp130 (Y759 in human gp130, Y757 in murine gp130) via its SH2 domain [77] and to gp130-associated JAKs. The kinase inhibitory region (KIR) of SOCS3 is involved in the interaction with JAKs but not by direct binding to the active site of the kinases as previously presumed. Instead, the KIR is involved in the recognition of a GQM-motif conserved in the kinase domains

Fig. 4. Cross-talk of IL-6, IL-1 and TNF signal transduction. IL-1 and TNF bind to their respective receptor complexes and initiate the activation of IKKa/b. Their downstream target NF-kB (p65/p50) can interact with STAT3 and affect expression of class I and class II acute-phase proteins. Additionally, activation of p38 MAPK and its downstream kinase MK2 inhibits IL-6-mediated signaling either by accelerating internalization of gp130 or by stabilizing SOCS3 mRNA.

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(JH1) of JAK1, JAK2 and TYK2. This interaction inhibits the kinase activity of JAKs. Therefore, the inhibition is non-competitive in contrast to the competitive inhibition by other known kinase inhibitors. This mode of action is specific for the Janus kinases JAK1, JAK2 and TYK2 but not JAK3 [78]. The p38/MK2 pathway has been recognized as important component regulating the increased TNFa-mediated expression of SOCS3. This effect is mediated by prolonged SOCS3 mRNA stability through inactivation of mRNA-destabilizing proteins such as tristetraprolin (TTP) [79,80] (Fig. 4). Forced expression of a constitutive active MKK6, the upstream kinase required for the activation of p38, almost completely abolished IL-6-mediated gene induction [81]. However, it was not corroborated whether this effect relies on increased SOCS3 expression or accelerated gp130 internalization. Furthermore, p38 activation allows the TNFa-mediated recruitment of the tyrosine phosphatase SHP2 to gp130 [82]. This protein has been shown to exert strong inhibitory activities on IL-6mediated signaling even in the absence of SOCS3 [83]. Further downstream cross-talk events between pro-inflammatory cytokines and IL-6-type cytokines have been shown for target gene induction, particularly for the acute-phase protein genes. Here, IL-1b strongly suppressed the IL-6-induced expression of the class II acute-phase proteins a2-macroglobulin or g-fibrinogen [67,70–72] (Fig. 4). This activity appears to be largely dependent on the cross-talk between NF-kB and STAT3. Investigations of the promoter region of both acute-phase protein genes revealed that the p65 subunit of NF-kB can compete with STAT3 for overlapping NF-kB/STAT3 DNA binding sites within the 50 -regulatory region [70,71]. Interestingly, this effect appears to be species-dependent since in contrast to the rat g-fibrinogen (FGG) gene the human gene lacks the overlapping DNA-binding sites in the 50 regulatory region. Furthermore, NF-kB activity inhibits IL-6 stimulated late phase STAT3 tyrosine phosphorylation [72]. This inhibitory effect might be explained by observations from Yoshida et al. [84]. They described a direct physical interaction between p65 and unphosphorylated STAT3. This sequestration of STAT3 would potentially reduce the amount of STAT3 available for IL-6 activation. NF-kB is not only a crucial component explaining parts of the suppressive effects of pro-inflammatory cytokines on IL-6mediated signal transduction. It can also cooperate with STAT3 to induce transcription of a number of target genes such as class I acute-phase proteins. Interestingly, while the interaction of p65 with STAT3 appears to prevent binding of STAT3 to classical STAT3 responsive elements in 50 regulatory regions of target genes [84], it seems to allow recruitment of STAT3 to non-consensus sequences in the promoter region of class I acute-phase protein genes such as serum amyloid A, ICAM-1 or IL-8 [84,85] (Fig. 4). Therefore, it might be concluded that the complex of p65, and STAT3 can act gene-dependently as a transcriptional activator or transcriptional repressor [86]. Taken together, these examples illustrate the complexity of intracellular cross-talk between IL-6 and pro-inflammatory cytokines such as IL-1b and TNFa. Even though enormous progress has been made in our understanding of antagonistic and synergistic activities of these cytokines, further studies are required to determine the transferability of these findings to other IL-6-type cytokines. Initial experiments indicate, e.g. that the MK2mediated accelerated internalization of gp130 affects signaling through IL-6 more strongly than signaling through OSM (own unpublished results, H.M.H.). This could imply that the reduction in gp130 cell surface expression affects cytokines signaling through a gp130 homodimer (lL-6, IL-11, IL-35) more strongly than cytokines signaling through a heterodimeric receptor complex (LIF, OSM, CNTF, CLC) and therefore change the responsiveness of cells to certain cytokines under pathophysiological conditions.

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6. Inter-familiar cross-talk between IL-6 and glucocorticoids The liver is also targeted by anti-inflammatory and metabolic stimuli such as glucocorticoids and glucagon and we are beginning to understand how these stimuli affect the IL-6 response. The endogenous glucocorticoid cortisol is synthesized in the adrenal cortex and is metabolized in the liver and secreted via the kidney. The release of glucocorticoids is controlled by the adrenocorticotropic hormone (ACTH) produced in the pituitary where the synthesis of ACTH is controlled by the circadian rhythm or induced in response to stress. ACTH is processed from preproopiomelanocortin (pre-POMC) and the secretion of ACTH is initiated by the corticotropin releasing hormone (CRH) which is secreted in the hypothalamus. Pre-POMC gene expression can be induced by IL-6-type cytokines as well as by leptin and is controlled by glucocorticoids in a negative feedback loop [87,88]. As stress hormones, glucocorticoids increase the glucose concentration in the blood and exert anti-inflammatory activities. The latter function is used pharmacologically to combat inflammatory diseases by the application of cortisol and synthetic cortisol derivates. Several mechanisms explaining the anti-inflammatory potential of glucocorticoids have been suggested [89–91]. Glucocorticoids inhibit the synthesis of IL-6 and induce apoptosis in dendritic cells, thymocytes, and mature T cells and affect the differentiation of T-cells. Furthermore, glucocorticoids inhibit the expression of pro-inflammatory mediators such as IL-1, IL-8, and inducible NO synthase (iNOS) and support the expression of anti-inflammatory proteins such as the IL-1-receptor antagonist (IL-1RA), the inhibitor of kB (IkB), and IL-10. They reduce the release of prostaglandins and leukotrienes and finally, glucocorticoids act synergistically on IL-6-induced acute-phase gene expression [92– 96]. The modulation of the acute-phase gene expression by glucocorticoids may help the organism to cope with an inflammatory stimulus. However, the molecular mechanisms of the interference of glucocorticoids with the expression of acute-phase genes are up to now not fully understood. On the one hand, glucocorticoids could interfere with the induction of IL-6-induced genes by acting on the specific promoters; on the other hand, glucocorticoids could act less gene-specific on IL-6-induced signaling cascade. Evidence is given for both scenarios. In the case of the acute-phase gene a2-macroglobolin (a2M) the promoter has been studied extensively and revealed the binding of a STAT3/glucocorticoid receptor complex to a STAT3-responsive element. Here, the glucocorticoid receptor acts as a transcriptional cofactor to increase a2M promoter activation [97]. Additionally, the formation of a complex consisting of STAT3 and the glucocorticoid receptor results in enhanced expression of the acute-phase proteins haptoglobin and metallothionein [98,99]. In addition, STAT5a and b activated by prolactin, growth hormone or erythropoietin interact with the activated glucocorticoid receptor. Complexes of the activated glucocorticoid receptor and STAT5 act cooperatively on STAT5-dependent gene induction independent of homodimerization and DNA binding of the glucocorticoid receptor [100–102]. Glucocorticoids seem to support the nuclear translocation of STAT5, the transcriptional activity of STAT5, and/or the STAT5 DNA-binding. Whereas the complex of STAT5 and the glucocorticoid receptor acts positively on promoters harboring STAT5 binding sites, promoters containing binding sites for glucocorticoid receptors are inhibited by glucocorticoid receptor/STAT5 complexes. In contrast to the activation of STAT5-dependent genes, this mechanism is independent of STAT5 tyrosine phosphorylation [90]. Whether these STAT5-dependent mechanisms of glucocorticoid action are also applicable for IL-6-dependent STAT3 activation in the liver remains

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to be analyzed carefully in detail, since recent studies demonstrated that constitutively activated artificial STAT3 mutants enhance the transcriptional activity of the glucocorticoid receptor [103]. Moreover, it will be interesting to see, if the recently described naturally occurring constitutive active gp130 variant will also lead to enhanced transcription of the glucocorticoid receptor [104,105]. Furthermore, long term treatment of hepatoma cells with glucocorticoids enhances the expression of the IL-6R in the liver [106] and thereby increases the expression of the acute-phase protein FGG. The enhanced expression of IL-6R enables hepatocytes to respond to supramaximal concentration of IL-6, indicating that the IL-6R is a limiting factor for acute-phase gene expression [107,108]. Through this mechanism glucocorticoids could increase acute-phase protein expression in the presence of high levels of IL6 during an acute inflammation. In addition to this long term effects, our own recent studies demonstrate that glucocorticoids influence the expression of SOCS3 in short time experiments [109]. Glucocorticoids reduce the protein expression of SOCS3 and thus enhance the IL-6-dependent expression of the class I and II acute-phase proteins serum amyloid A (SAA), antichymotrypsin (ACT), and FGG in hepatocytes [109]. The enhanced hepatic acute-phase gene expression correlates with enhanced STAT3 activation. In line with these observations, glucocorticoids do not enhance the expression of acute-phase proteins in hepatocytes expressing mutants of gp130 lacking the SOCS3 binding site (Y757F) and thereby being resistant to the inhibition by SOCS3. Furthermore, STAT3 activation in SOCS3deficient cells was not enhanced by glucocorticoids but in corresponding wild-type cells [109]. Importantly, in vivo experiments indicate that IL-6-induced expression of SAA is affected by glucocorticoids in wild-type mice but not in mice expressing the mutated receptor chain gp130 (Y757F) in hepatocytes. The binding of SOCS3 to the receptor complex also appeared to be crucial for the enhanced a2M promoter activation in response to IL-6 and glucocorticoids. This indicates that the expression of a2M is controlled by glucocorticoids by at least two mechanisms. First the reduction of SOCS3 expression [109] and second the formation of a STAT3/glucocorticoid receptor complex at the promoter as described before [97]. The molecular mechanisms of how glucocorticoids affect SOCS3 expression are still under investigation. Paul et al. suggest that glucocorticoids act on the rat SOCS3 promoter without direct binding of the glucocorticoid receptor to the DNA [110]. However, the studies of Dittrich et al. did not present any evidence for glucocorticoids acting on murine SOCS3 promoter activation [109]. Whether these discrepancies reflect species-specific differences remains to be clarified. Nevertheless, in agreement with all these studies Croker et al. observed a strong IL-6-induced proinflammatory response in mice lacking hepatic SOCS3 expression [76]. Thus, SOCS3 fulfills an important function in glucocorticoiddependent up-regulation of IL-6-induced acute-phase gene expression. However, the existence of several independent mechanisms of glucocorticoid-induced enhanced acute-phase response highlights the importance of this cross-talk. Interestingly, the cross-talk between glucocorticoids and IL-6 is not restricted to the liver. Kinter et al. could show that IL-6 and glucocorticoids synergistically induce the HIV expression in latently infected cells by an up to now unknown posttranscriptional mechanism [111]. Furthermore, Ladenburger et al. demonstrated that glucocorticoids enhance the expression of the IL-6R in embryonic bronchial cells resulting in increased expression of IL-6induced surfactant proteins and improved development of the lung [112]. Also estrogen interferes with IL-6 signaling. Estrogen reduces IL-6 levels in females explaining increased IL-6 levels in the menopause. These differences may account for the gender differences in liver cancer and osteoporosis [113,114]. In summary

the cross-talk between IL-6 and glucocorticoids is neither explainable by a single mechanism nor is it restricted to a specific cell type. The different mechanisms of glucocorticoid action on IL-6 signaling either by affecting IL-6R expression, by controlling promoter activation of the specific target genes, or by regulating SOCS3 expression, currently complicates the generation of a clear picture. Obviously, previous studies on the glucocorticoid–IL-6 cross-talk need to be re-evaluated in respect to the recent findings. Whereas most of the studies have been performed on the IL-6– glucocorticoid cross-talk, additional emphasis needs to be placed on the cross-talk of the other IL-6-family members as well. 7. Inter-familiar cross-talk of IL-6 and G-protein-coupled receptors Besides glucocorticoids, glucagon is another important hormone controlling the homeostasis of glucose in response to starvation and stress. Pre-proglucagon is synthesized in the a-cells of the pancreas. Fully processed glucagon is a peptide hormone of 29 amino acids, which acts on hepatocytes to release glucose from glycogen in case of a low glucose concentration in the blood. In parallel, glucagon inhibits the production of glycogen. Glucagon signals through 7-transmembrane receptors coupled with trimeric G-proteins and activates adenylate cyclase and phospholipase C. Growing evidence exists for a cross-talk of signaling cascades initiated by G-protein-coupled receptors (GPCRs) and the IL-6 signaling pathway. Two recent studies address glucagon-mediated inhibition of IL6-induced gene expression in hepatocytes. Both studies vary in respect to the suggested involvement of SOCS3. Gaudy et al. found that glucagon induces the expression of SOCS3 via exchange protein activated by cAMP (Epac) and ras-related protein 1 (Rap1) [115]. Epac is a guanine nucleotide exchange factor for the small Gprotein Rap1. The authors suggest that SOCS3 counteracts glucagon-induced, protein kinase A (PKA) dependent gene induction by interfering with the phosphorylation of PKA substrates such as cAMP response element-binding protein (CREB). The authors favor an interaction of SOCS3 and the catalytic subunit of PKA to inhibit PKA activity [115]. Khouri et al. observed a specific inhibition of IL-6-induced MAPK activation, whereas STAT3 activation was not affected by glucagon [116]. In line with the specific inhibition of the MAPK cascade the expression of the ERKdependent acute-phase gene tissue factor pathway inhibitor (Tfpi)2 was affected by glucagon, however the expression of the ERK-independent acute-phase gene FGG was not. The elaborated molecular mechanism hints to a redundant contribution of PKA and Epac for glucagon-dependent repression of MAPK activation and inhibition of Tfpi2 gene expression (Fig. 5). The inhibition of the MAPK cascade and Tfpi2 expression by glucagon was also observed in the presence of the inhibitor of protein biosynthesis cycloheximide [116]. As SOCS3 expression depends on de novo protein synthesis these results argue against the involvement of SOCS3. Similar studies on the cross-talk between cAMP- and IL-6 signaling were performed in human dermal fibroblasts and human umbilical vein endothelial cells [117–119]. These studies address the inhibition of the IL-6-induced MAPK dependent MCP1/CCL2 gene induction by prostaglandin E1 (PGE1) [117] or forskolin, which activates the adenylyl cyclase [118], respectively. PGE1 inhibits specifically the IL-6-induced MAPK activation but not the activation of STAT3 in human dermal fibroblasts again arguing against the involvement of SOCS3. This inhibition depends on the activation of PKA, but is independent of Epac [117]. However studies in human vascular endothelial cells demonstrated that forskolin induces SOCS3 expression in an Epac dependent manner [118,119] (Fig. 5).

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Fig. 5. Cross-talk of GPRC-mediated and IL-6 signaling. Overview of potential interconnections of both pathways as referred in the text. Note that not all connections are realized by all cellular and experimental/stimulatory systems. SOCS-dependent and SOCS-independent mechanisms have been described. In HUVEC, EPAC, activated by cAMP induces SOCS3 via Rap1 activation in [118,119] which counteracts IL-6 signaling by inhibiting JAK kinases. In primary fibroblasts and hepatocytes cAMP (induced by prostaglandin E1 or glucagon, respectively) inhibits specifically IL-6-dependent MAPK activation without affecting STAT3 activation by SOCS3-independent mechanisms. Whereas prostaglandin E1 acts through PKA to inhibit cRAF in primary fibroblasts [117] glucagon acts redundantly through PKA and EPAC in hepatocytes [116]. In both cases IL-6-induced MAPK-dependent gene induction is impaired whereas STAT3-dependent gene induction is not affected. In contrast, SOCS3 has also been suggested to block PKA activity which would block CREB-dependent gene induction [115].

Although these discrepancies cannot be solved without additional experiments one can argue that cell-type specific mechanisms may contribute to the opposing observations made. Furthermore, IL-6-induced gene expression may be controlled by G-protein coupled receptor signaling in a cooperative manner through immediate, SOCS3-independent inhibition of MAPK activation and later SOCS3-dependent mechanisms. Whether other IL-6-type cytokines are also influenced by or influencing signaling via glucocorticoids or GPCRs is, however, not known.

8. Inter-familiar cross-talk of IL-6 and receptor tyrosine kinase signaling: taming insulin Besides glucagon and glucocorticoids, the peptide hormone insulin is a central mediator in glucose homeostasis. Insulin resistance and type II diabetes as a result of caloric overconsumption are a major health problem in the western world and obesity is often associated with low grade inflammation [120,121]. Adipose tissue as an endocrine organ is capable of producing mediators termed adipokines, such as TNFa [122] and IL-6 [123]. The role of IL-6 in glucose homeostasis is an issue of a long-standing debate [124,125]. High fat diet induces the production of IL-6 by adipocytes through the activation of c-Jun N-terminal kinase (JNK)-1 and there are clear indications for the induction of hepatic insulin resistance through adipocyte-derived IL-6 [126–128]. In this context it is considered as a paradox, that exercise mediated IL-6 secretion by skeletal muscle seems not to contribute to insulin resistance. Here, IL-6 is protective mediating insulin-sensitizing effects [125]. Furthermore, IL-6 deficient mice become overweight arguing for a function of IL-6 in the regulation of body weight [129]. IL-6 deficiency is accompanied by hepatosteatosis, liver inflammation and insulin resistance [130]. Hepatic IL-6 signaling

limits liver inflammation and by this mechanism protects from systemic insulin resistance [131]. IL-6 interferes with insulin signaling mainly through the induction of the feedback inhibitors SOCS1 and SOCS3 [132,133]. SOCS3 is not only recruited to gp130, but also to the phosphorylated tyrosine Y960 of the insulin receptor apparently without inhibition of the insulin receptor tyrosine kinase activity. However, SOCS3 competitively blocks the binding and subsequently the phosphorylation of STAT5 at Y960 [134]. Through their SOCS box motif, SOCS proteins can interact with the elongin BC ubiquitin ligase complex to target substrates for degradation by the proteasome. Through this adaptor function SOCS3 and SOCS1 mediate proteasomal degradation of the insulin receptor substrates IRS1 and IRS2 [132] resulting in the shutdown of most aspects of insulin and insulin-like growth factor signaling. Moreover, SOCS1 and SOCS6 can inhibit insulin receptor kinase activity [135]. Thus, SOCS proteins interfere with insulin signaling by multiple mechanisms. From genetic mouse models, it is evident that SOCS3 is more relevant than SOCS1 in IL-6 mediated hepatic insulin resistance [136–138]. SOCS3 not only regulates insulin signaling in hepatocytes but also in other cell types such as adipocytes [139]. Recent work confirms a functional role of IL-6 in insulin resistance [140]. Matsubara et al. identified progranulin as an adipokine that mediates high fat diet induced insulin resistance through the induction of IL-6 production by adipocytes. Blockade of IL-6 with a neutralizing antibody improved insulin sensitivity under progranulin treatment. Neutralization of IL-6 has been shown previously to be beneficial in models of obesity-induced insulin resistance [126]. On the other hand, it has been recently shown that IL-6 increases the production of glucagon-like peptide 1 (GLP-1) from intestinal L-cells and pancreatic alpha-cells leading to increased insulin production and improved glucose tolerance [141]. Thus, the

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debate on the role of IL-6 in insulin resistance and type II diabetes is ongoing. The various sources of IL-6 and the different target organs and cell types might differentially contribute to deleterious and protective effects of this cytokine in the metabolic syndrome. For the IL-6-type cytokine OSM, it was recently shown that it might be involved in hepatic insulin resistance through attenuation of insulin-dependent Akt activation. Thereby, induction of the enzyme glucokinase is prevented. Furthermore, expression of key enzymes of hepatic lipid metabolism was suppressed [142]. By acting on the hypothalamic regulation of appetite but also on the metabolism of muscle, CNTF protects from obesity and insulin resistance [143]. These two examples show that individual IL-6type cytokines interfere differentially with metabolism and insulin action.

9. Conclusions and future directions IL-6 has been described almost 30 years ago. With the beginning of the post-genomic era the family of IL-6-type cytokines was completed with the discovery of IL-30 by database screening. However, the limited gene number of cytokines does not mean that nature has not invented alternative ways to recombine existing proteins with novel functions. This was illustrated by the recent discovery of IL-35, bridging the IL-6 and IL-12 families. It will not come as a surprise if nature’s ability to develop novel functions for existing proteins will lead to the identification of additional cytokine/cytokine receptor combinations. This complexity is easily surmounted by the ability of a cell to integrate and fine-tune multiple signals and signaling pathways. Even though research on cross-talk has been studied intensively for IL-6 itself, it remains anecdotic in case of most other IL-6-type cytokines. Therefore further studies are required and systems biology is in demand to support these studies with complex pathway design and modeling approaches. IL-6 is one of the major novel targets for the treatment of patients with chronic inflammatory diseases. Therapies with tailor-made monoclonal antibodies specifically targeting IL-6 did, however, not consider complex cross-talk in vivo, which might contribute to the pro- and anti-inflammatory/regenerative properties of IL-6. Patients under treatment with the neutralizing anti-IL-6R mAb tocilizumab developed weight gain and increased levels of triglycerides and cholesterol, showing that caution is necessary when cytokines are blocked over long periods of time which is required for therapy of autoimmune diseases [144]. Furthermore, blockade of a single cytokine can be desirable at the site of inflammation but devastating at off-target sites. Future therapeutic strategies should therefore take into consideration that cytokines act in complex networks and should be inhibited locally rather than systemically and if possible even not on all cells at inflammatory sites.

Acknowledgements This work is supported in part by grants from the Deutsche Forschungsgemeinschaft, Bonn, Germany (JS: DFG SCHE 907/2-1; SRJ SFB877, project A1; FS: SFB542, projects TP 2 and TP4; HMH: FZ82; GMN: SFB542, projects A1 and B12; and by the Cluster of Excellence ‘Inflammation at Interfaces’). References [1] [2] [3] [4]

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C. Garbers et al. / Cytokine & Growth Factor Reviews 23 (2012) 85–97 [133] Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, et al. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. The Journal of Biological Chemistry 2003;278:13740–46. [134] Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, Van Obberghen E. SOCS-3 is an insulin-induced negative regulator of insulin signaling. The Journal of Biological Chemistry 2000;275:15985–91. [135] Mooney RA, Senn J, Cameron S, Inamdar N, Boivin LM, Shang Y, et al. Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. The Journal of Biological Chemistry 2001;276:25889–93. [136] Emanuelli B, Macotela Y, Boucher J, Ronald Kahn C. SOCS-1 deficiency does not prevent diet-induced insulin resistance. Biochemical and Biophysical Research Communications 2008;377:447–52. [137] Sachithanandan N, Fam BC, Fynch S, Dzamko N, Watt MJ, Wormald S, et al. Liver-specific suppressor of cytokine signaling-3 deletion in mice enhances hepatic insulin sensitivity and lipogenesis resulting in fatty liver and obesity. Hepatology 2010;52:1632–42. [138] Torisu T, Sato N, Yoshiga D, Kobayashi T, Yoshioka T, Mori H, et al. The dual function of hepatic SOCS3 in insulin resistance in vivo. Genes to Cells 2007;12:143–54. [139] Shi H, Tzameli I, Bjorbaek C, Flier JS. Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling. The Journal of Biological Chemistry 2004;279:34733–40. [140] Matsubara T, Mita A, Minami K, Hosooka T, Kitazawa S, Takahashi K, et al. PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue. Cell Metabolism 2012;15:38–50. [141] Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nature Medicine 2011;17: 1481–9. [142] Henkel J, Ga¨rtner D, Dorn C, Hellerbrand C, Schanze N, Elz SR, et al. Oncostatin M produced in Kupffer cells in response to PGE2: possible contributor to hepatic insulin resistance and steatosis. Laboratory Investigation 2011;91:1107–17. [143] Ahima RS. Overcoming insulin resistance with CNTF. Nature Medicine 2006;12:511–2. [144] Melton L, Coombs A. Actemra poised to launch IL-6 inhibitors. Nature Biotechnology 2008;26:957–9. Christoph Garbers received his diploma degree in Pharmacy in 2007 at the University of Kiel, Germany, and his licensure as pharmacist in 2008. He joined the group ‘‘Cytokine and Metalloproteinase Research’’ at the Institute of Biochemistry of the University of Kiel in 2008 and obtained his Dr. rer. nat. (Ph.D.) in 2011. He then moved to the Heinrich-Heine-University Du¨sseldorf, Germany, and works since 2011 at the Institute of Biochemistry and Molecular Biology II as a postdoctoral research associate. His current interests are focussed on limited proteolysis of cytokine receptors and signal transduction of IL-6 type cytokines. Heike M. Hermanns finished her diploma study for Biology in 1996 at the RWTH Aachen University, Germany and obtained her Dr. rer. nat. (Ph.D.) in 2000. After her Ph.D. she became a group leader and later assistant professor in the group of Peter C. Heinrich (Institute for Biochemistry, RWTH Aachen University Hospital), where she focussed her studies on OSMand IL-31-mediated signal transduction and physiology. In 2007 she moved to the Julius-Maximilians-University of Wu¨rzburg, Germany, where she is currently the junior group leader of the section ‘‘Inflammatory Cytokine Signaling’’ at the Rudolf Virchow Center, the DFG Research Center for Experimental Biomedicine. Fred Schaper received in 1992 a Diploma in Biology, and the Dr. rer. nat. (Ph.D.) degree from the Technical University Carolo Wilhelmina of Braunschweig, Germany in 1996. The practical parts of both studies had been realized at the German Research Centre for Biotechnolgy (GBF), now Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany and within the framework of an internship at the Technion University, Haifa, Israel. He became junior research group leader at

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the Department of Biochemistry and Molecular Biology at the RWTH University, Aachen, Germany in 1996, received the venia legendi for Biochemistry and Molecular Biology in 2002 and became assistant professor at the same location in 2005. Fred Schaper has been appointed to a full professor (W3) at the Department of Biology of the Otto-von-Guericke University, Magdeburg, Germany and chairs the Department of Systems Biology since 2010. His interests are focussed on the regulatory and dynamic aspects of IL-6 signaling and the cross-talk of IL-6 with other cytokines and hormones.

¨ ller-Newen finished his diploma studies in Gerhard Mu Chemistry in 1989 and obtained his Dr. rer. nat. (Ph.D.) at the University of Cologne in 1993 on enzymes involved in the oxidation of fatty acids. Since 1994 his main research interests are structure/function of IL-6type cytokines and their receptors, inhibition of these cytokines by receptor fusion proteins and the dynamics of JAK/STAT signal transduction. He is currently working as an associate professor at the Institute of Biochemistry and Molecular Biology at the RWTH Aachen University.

¨ tzinger studied chemistry at the University Joachim Gro of Wuppertal and the RWTH-Aachen, where he got his Dr. rer. nat. (Ph.D.) in 1991. After a one year postdoc at the University of Groningen, Netherlands with an EUScholarship, he worked until 2001 at the Biochemical Institute at the RWTH-Aachen, where he obtained his Habilitation in 1998. Since 2001 he is group leader of structural biology at the Biochemical Institute of the Christian-Albrechts-University of Kiel. His current interest is centered around the structural biology of antimicrobial peptides, cytokines and their receptors.

Stefan Rose-John studied biology at the University of Heidelberg in Germany where in 1982 he obtained his Dr. rer. nat. (Ph.D.). After a postdoctoral stay in the USA he worked for three years at the German Cancer Research Center in Heidelberg. In 1988 he joined the Institute of Biochemistry of the RWTH-Aachen, Germany where in 1992 he obtained his Habilitation. In 1994, he accepted a professorship for Pathophysiology at the University of Mainz, Germany and since 2000 he is full professor and director at the Institute of Biochemistry of the University of Kiel. He is author of more than 260 original articles and 45 reviews. His current interest is centered around the molecular biology and pathophysiology of Interleukin-6 and related cytokines.

¨ rgen Scheller finished his diploma study of Biology in Ju 1997 at the Georg-August University of Go¨ttingen, Germany and obtained his Dr. rer. nat. (Ph.D.) in 1999. He joined the group ‘‘Phytoantibodies’’ at the Leibniz-Institut IPK in Gatersleben, Germany in 1999. From 1999 to 2002 he works on spider silk proteins from transgenic plants. In 2002 he became an assistant professor in the Biochemical Institute at ChristianAlbrechts-Universita¨t of Kiel, Germany. In 2008 he became W2-Professor for ‘‘Cytokine Signaling’’ within the Cluster of Excellence ‘‘Inflammation at Interfaces’’ at Christian-Albrechts-Universita¨t of Kiel, Germany. In 2010 he moved to the Heinrich-Heine-University and became the director of the Institute of Biochemistry and Molecular Biology II as a W3-Professor. His present interests are focussed on in vitro and in vivo studies of IL-6-type cytokines.