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IL-18 and skin inflammation
Autoimmunity Reviews 9 (2009) 45–48
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Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
IL-18 and skin inflammation☆ Miriam Wittmann a,b,⁎, Andrew Macdonald a, Julius Renne b a b
Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK Department of Immunodermatology and Allergy Research, Hannover Medical School, Hannover, Germany
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 1 March 2009 Accepted 4 March 2009 Available online 11 March 2009
IL-18 belongs to the IL-1 family of cytokines and has recently regained interest in the context of inflammasome activation. The inflammasome dependent caspase 1 cleaves pro-IL-18 into the active form — similar to what is known for IL-1ß. Still, the action and importance of IL-18 are not completely understood. There are several indications that it plays a pathogenetically important role in chronic inflammatory conditions of epithelial organs (such as skin, gut, kidney) and importantly also in responses against self. Here, we summarise current knowledge on the role of IL-18 in human skin inflammation with a focus on its role in Cutaneous Lupus Erythematosus (CLE). There is evidence that IL-18 plays a role in CLE upstream of TNFα. In CLE but not normal keratinocytes IL-18 strongly induces TNFα release, which then results in apoptosis. Blocking TNFα in vitro prevents apoptosis of keratinocytes but anti-TNFα therapy is not applicable in LE conditions. We will discuss potential approaches to control IL-18 in skin inflammation. © 2009 Elsevier B.V. All rights reserved.
Keywords: Interleukin-18 Skin inflammation Lupus erythematosus
Contents 1. IL-18: an overview . . . . . . . . . 2. Interleukin-18 in skin inflammation 3. Autoimmune inflammatory diseases 4. Targets for therapy . . . . . . . . . Take-home . messages . . . . . . . . . . References . . . . . . . . . . . . . . .
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1. IL-18: an overview IL-18 belongs to the IL-1 family of cytokines, which has recently been re-named due to the addition of new family members (for review: [1]) and now consists of IL-1F1 to IL-1F11. The powerful proinflammatory IL-1 family members, in particular IL-1ß (IL-1F1) and IL18 (IL-1F4) are known to be tightly controlled and are synthesised as inactive precursors. Next to IL-1ß and IL-18, the recently described IL-1 family members – IL-33 (IL-1F11) and IL-1F7 – have been reported to also be cleaved by caspase 1 into biologically active cytokines. This enzyme is part of the so called “inflammasome”, a macromolecular complex formed within the cytoplasm of the cell. Intracellular nucleotide binding oligomerisation domain-like receptor (NLR)
☆ This work was supported by DFG grant Wi-1822/5-1. ⁎ Corresponding author. University of Leeds, Faculty of Biological Sciences Institute of Molecular and Cellular Biology Leeds, LS2 9JT, UK. Tel.: +44 113 343 3101; fax: +44 113 343 3046. E-mail address: [email protected] (M. Wittmann). 1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2009.03.003
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ligands activate caspases through the assembly of inflammasomes and recent reports have shown that all of the essential inflammasome components are expressed in human primary keratinocytes [2–4] — the cells which form the outermost skin layer. NLRs not only sense pathogens but also tissue injury, metabolic stress or “endogenous danger” (danger-associated molecular patterns — DAMPs). In contrast to the assembly of IL-1ß, which is controlled by two signals (induction of mRNA by Toll-like receptor complexes plus inflammasome activation), pro-IL18 is constitutively expressed and therefore only caspase 1 activation is needed to produce mature IL-18. Watanabe et al. [5] demonstrated that epidermal activation of the inflammasome by DAMPs influences the reaction towards simultaneously presented allergens enabling a switch between sensitisation and tolerance induction. As a consequence IL-18 is likely to be an important factor in the initiation of inflammation and autoimmune disorders [6]. In skin immunopathophysiology keratinocytes play a prominent role as effective producers of antimicrobial defensins, chemokines and cytokines [7,8]. IL-18 is produced by keratinocytes [9–12] and in addition Langerhans cells (LC) located in the epidermis [13] and
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M. Wittmann et al. / Autoimmunity Reviews 9 (2009) 45–48
Fig. 1. A. Histopathological features of CLE include prominent changes at the dermoepidermal interface such as hydropic degeneration of the basal epithelial layer. Apoptotic keratinocytes in the epidermis may be numerous. In addition, the lymphocytic infiltration (here: CD8 T cells are stained in red) is confined to the upper dermis and often appears band-like. Hyperkeratosis and follicular plugging is mainly seen in chronic discoid forms of LE. B. Immunopathogenesis: In CLE apoptotic keratinocytes are found mainly in the basal layer of the epidermis. Altered IL-18 sensitivity with high IL-18R expression on keratinocytes seems characteristic for CLE. IL-18 – which is expressed in the epidermis of skin lesions – induces epidermal production of the chemokine CXCL10 which favours the attraction of IFNγ producing lymphocytes. T cells accumulate near the dermoepidermal border in close vicinity to keratinocytes. Furthermore, IL-18 results in the release of TNFα from activated keratinocytes. TNFα acts in an autocrine feedback loop to induce apoptosis in neighbouring epidermal cells. Due to a clearance deficiency in lupus conditions, apoptotic cells are not removed, undergo “secondary necrosis” and as a consequence may release danger associated molecular patterns (DAMPs) such as HMGB1 or HSPs into the extracellular space. When immunocompetent cells encounter (formerly intracellular auto-)antigens in the context of DAMPs they may switch from a tolerant (normally induced by apoptotic cells) toward an auto-immune response/or cytotoxicity [36], which may also be favoured by the absence of Treg cells in CLE skin lesions [37]. DAMPs may also contribute to further activate keratinocytes to express chemokines and cytokines thus sustaining local inflammation. A chemotactic activity of IL-18 on DC [15] may also contribute to the accumulation of plasmacytoid Dendritic Cells (pDC) in the upper dermis. pDC have been found in CLE [38] and are known producers of type I IFNs which in turn activate keratinocytes to, amongst others, express IL-18R on their surface [23]. Due to the presence of inflammatory mediators the integrity of the basement membrane is destroyed facilitating influx of inflammatory cells.
dermal dendritic cells (DC) in the skin are also able to produce mature IL-18 in response to inflammatory stimulation, which in turn contributes to the regulation of LC/DC migration [14,15]. Although inflammasome components are expressed in human kerationcytes [2] and the presence of bioactive IL-1ß and IL-18 in the supernatant of activated keratinocytes has clearly been shown [2,9], it is still not clear how exactly these molecules are activated by epithelial cells. Cleavage of the pro-IL-1ß/pro-IL-18 by intracellular caspase 1 has not been demonstrated in keratinocytes. Although an extracellular cleavage by mast cell chymase or chymotryptic epidermal enzymes [16,17] and the release of inflammasome components including caspase 1 has been shown for keratinocytes and other cells [2,18], the processes involved in the generation of epidermal mature IL-1ß and IL-18 remain to be fully elucidated. Certainly, epithelial cells may not produce mature IL18 under steady-state-conditions but rather in an activated state as seen in the context of inflammation. IL-18 plays an important pro-inflammatory role [19] and is involved in the induction of inflammatory mediators as well as regulation of the cytotoxic activity of Natural Killer (NK) cells and T cells. Furthermore, IL-18 was found to support the differentiation and activation of different T helper (Th) cell subsets depending on the surrounding cytokine profile [20]. For example, in the presence of IL12 a Th1 response is favoured (e.g. in chronic eczema or psoriatic skin inflammation), in its absence a Th2 response may be enhanced, such as seen in cutaneous T cell lymphoma associated skin inflammation [21] or acute eczema. Therefore IL-18, together with its activation by the inflammasome, bridges the innate and adaptive immune responses [1]. Keratinocytes can directly respond to IL-18 [22,23]. The IL-18R needs two signals to be upregulated in keratinocytes from healthy patients [23], one of which has to be an interferon (IFN) and possible second signals include TNFα or dsRNA. Keratinocytes respond to IL-18 with the production of CXCL10, a chemokine that mainly attracts IFNγ producing, CXCR3 positive Th1 cells [22,23]. Furthermore, IL-18 can up-regulate the expression of MHC class II molecules on keratinocytes [23], which may have an important role in situations where the skin is infected with superantigen producing staphylococcus aureus. In the presence of superantigen MHC class II positive keratinocytes can
further enhance IFNγ production by lymphocytes with the appropriate Vß chain. 2. Interleukin-18 in skin inflammation IL-18 expression and effector functions have been described in inflammatory diseases across a broad range of tissues (reviewed in [19]) including joints [24], kidney [25] and the skin. Immunohistology and RT-PCR analysis demonstrate higher levels of expression of both IL-18 and IL-18R in lesional skin, including cutaneous lupus erythematosus (CLE), psoriasis, GvHD, cutaneous T cell lymphoma and atopic dermatitis (AD) compared to healthy skin [4,12,21,23,26]. However, a drawback of these studies is that the methodical approaches were based on either PCR or immunohistology, which do not distinguish between pro-IL-18 and mature IL-18. AD, one of the most prevalent skin diseases today could be linked to polymorphisms of the IL-18 gene [27]. In murine AD models IL-18 seems to play an important role in acute eczema but data for the skin compartment in human acute AD are lacking. As for the chronic phase of eczema, predominated by IFNγ, we were able to show that autologous T cells produced IFNγ in the presence of IL-18 stimulated keratinocytes and SEB [23]. 3. Autoimmune inflammatory diseases A number of studies point to the relevance of IL-18 in lupus pathology (for review: [6]), as well as other autoimmune inflammatory diseases. Our data, comparing IL-18 expression in lesional skin of CLE to acute AD point to high IL-18 expression levels in CLE skin lesions. Keratinocytes from patients with CLE show a proinflammatory response pattern distinct from normal keratinocytes in which IL-18 seems to play a significant role Fig. 1. In CLE keratinocytes IL-18R is easily upregulated in the presence of only one signal. IFNγ as well as TNFα alone is able to further up-regulate IL-18R, which already shows a higher basal expression in CLE keratinocytes compared to healthy donors. The underlying reason for high basal IL-18R expression is not clear to date. Nevertheless, the effect of IL-18 on CLE keratinocytes is high production of TNFα and induction of apoptosis which is not seen
M. Wittmann et al. / Autoimmunity Reviews 9 (2009) 45–48
in healthy keratinocytes. We were able to show that IL-18 dependent apoptosis was mediated by autocrine TNFα and diminished IL-12 expression — the latter has been shown previously to protect keratinocytes from TNFα or UV mediated apoptosis [28,29]. Overexpression of TNFα has been recognised for LE skin lesions [30]. In accordance with previous reports on CLE [30], we could not find a link to the known TNF-308 promoter polymorphism. However, in both studies mentioned, the number of patients included was low. An unanswered question is whether the high IL-18 susceptibility and high TNFα production is a genetic or epigenetic feature of epithelial cells. Of note, we cultured our keratinocytes from epidermal stem cells of the hair follicle, thus these cells were derived from non-lesional skin of LE patients. Subclinical involvement of the scalp region is however possible as many of the patients included in the study are highly UV sensitive and UV light is a known trigger factor of LE. Of note, UV has been recognised as an inducer of the inflammasome [2,31]. The cells maintained their phenotype with high IL-18R expression and TNFα production also after repeated thawing and re-culture cycles. Taken together, in CLE IL-18 may occupy a proximal position in the proinflammatory cytokine cascade. So far, we do not know whether the increased TNFα production upon IL-18 stimulation in CLE keratinocytes is due to increased IL-18 sensitivity or altered TNFα regulation. It has been proposed that IL-18 itself may play a role in the establishment of (auto)-reactivity. In lupus conditions the noninflammatory clearance of apoptotic cells is impaired [32] and it has been proposed that the increased rate of apoptosis increases the chance of leakage of intracellular antigens. A number of studies indicate that DAMPs such as high-mobility group box-1 (HMGB1) [33], ATP and heat shock protein 70 (HSP70) may be released from intracellular compartments. Encounter of both an intracellular antigen and a DAMP (which activates the inflammasome and leads to caspase 1 dependent release of mature IL-18 and IL-1ß) by immunocompetent cells may trigger an autoimmune response. It remains to be shown whether autoimmune phenomena also described for AD and psoriasis are linked to inflammasome activation and the presence of IL-18 in the tissue. Another hint for IL-18 playing an important and potentially harmful role in inflammatory disorders of the skin is the fact that freshly isolated and IFNγ stimulated epidermal stem cells seem to have switched off the capacity to express IL-18 while still expressing CXCL10 and other cytokines [10]. These studies have however been performed outside the stem cell niche and the cells underwent only limited purification by adherence to integrin ß1 ligands. It remains to be determined whether absence of IL-18 is important for the so-called protected stem cell niche. Thus far, we lack the appropriate experimental systems to analyse in detail the hierarchy of mediators in human inflammatory conditions. Unfortunately, disease models in rodents often fail to depict the human situation and many of the most important immunoregulatory mediators are fundamentally different between mice and men. As outlined in greater detail by Faustin and Reed [31], there are important differences between the two species with respect to NLR-family proteins and inflammasome associated cytokines. For example human but not murine keratinocytes produce pro-IL-1ß.
4. Targets for therapy For LE pathology, it is not clear to date, if epithelial cells release the IL-18 counter-regulating molecules IL-18BP and IL-1F7. Also, IL-33 which favours Th2 mediated responses could potentially be of benefit if upregulated in LE pathology. Furthermore, the source of epidermal IL-1 and IL-18 and their activation remain to be clearly deciphered. Importantly, the reason why CLE keratinocytes react to IL-18 with high TNFα release is unknown. We need to understand these issues in CLE
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pathology in order to understand the contribution of tissue resident cells to immunopathology and to identify therapeutic targets. With the data available to date, targeting IL-18 bioactivity may be a promising therapeutic intervention in CLE conditions. It has become clear that targeting TNFα by anti-TNFα therapy exacerbates (or induces) LE conditions with increases seen in serum anti-dsDNA autoantibodies. Therefore, IL-18 might be a better target in the epidermis as it may only abrogate autocrine TNFα release, thus reducing the apoptotis rate of keratinocytes. An interesting molecule in this context is IL-18 binding protein (IL-BP), an endogenous antagonist with high neutralising capacity for IL-18. IL-18BP binds to mature IL-18, but not pro-IL-18, with high affinity and prevents its interaction with cell surface receptors [1]. In healthy human epithelial cells, IFNγ is known to induce the release of IL-18BP [34]. In some autoimmune diseases an IL-18/IL-18BP imbalance has been described. Data for LE conditions are lacking so far. Of note is the fact that another IL-1 family member, IL-1F7, has been demonstrated to enhance the inhibitory effect of IL-18BP and recent data in the murine system suggest that it may also act as a transcriptional modulator reducing IL6, TNFα and IL-1α [35]. Another target may be caspase 3 which cleaves IL-18 into inactive forms. It may be argued that previous attempts with caspase-1 inhibitors have not been terribly successful in pre-clinical trials for connective tissue diseases. This could be due to the fact that other enzymes are able to cleave pro-IL-18 and also that other IL-1 family members, with potentially antagonistic action, are also cleaved by caspase 1 (IL-1F7, IL-33). This points to the fact that inflammasome inhibitors may also fail to show beneficial effects with regard to IL-18 counter-regulation but this remains to be shown. Take-home messages • IL-18 is found in chronic inflammatory skin conditions • It is still unclear how pro-IL-18 is activated in the epidermis • Keratinocytes from Cutaneous Lupus Erythematosus (CLE) patients overexpress IL-18R • In CLE IL-18 may act upstream of TNFα with regard to apoptosis induction • Manipulating the balance between IL-18 and its endogenous antagonists IL-18BP / IL-1F7 may be a promising therapeutic approach in lupus conditions References [1] Arend WP, Palmer G, Gabay C. IL-1, IL-18, and IL-33 families of cytokines. Immunol Rev 2008;223:20–38. [2] Feldmeyer L, Keller M, Niklaus G, Hohl D, Werner S, Beer HD. The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes. Curr Biol 2007;17:1140–5. [3] Harder J, Nunez G. Functional Expression of the Intracellular Pattern Recognition Receptor NOD1 in Human Keratinocytes. J Invest Dermatol 2009 [Electronic publication ahead of print]. [4] Wang D, Drenker M, Eiz-Vesper B, Werfel T, Wittmann M. Evidence for a pathogenetic role of interleukin-18 in cutaneous lupus erythematosus. Arthritis Rheum 2008;58:3205–15. [5] Watanabe H, Gehrke S, Contassot E, Roques S, Tschopp J, Friedmann PS, et al. Danger signaling through the inflammasome acts as a master switch between tolerance and sensitization. J Immunol 2008;180:5826–32. [6] Boraschi D, Dinarello CA. IL-18 in autoimmunity: review. Eur Cytokine Netw 2006;17:224–52. [7] Albanesi C, Scarponi C, Giustizieri ML, Girolomoni G. Keratinocytes in inflammatory skin diseases. Curr Drug Targets Inflamm Allergy 2005;4:329–34. [8] Wittmann M, Werfel T. Interaction of keratinocytes with infiltrating lymphocytes in allergic eczematous skin diseases. Curr Opin Allergy Clin Immunol 2006;6:329–34. [9] Naik SM, Cannon G, Burbach GJ, Singh SR, Swerlick RA, Wilcox JN, et al. Human keratinocytes constitutively express interleukin-18 and secrete biologically active interleukin-18 after treatment with pro-inflammatory mediators and dinitrochlorobenzene. J Invest Dermatol 1999;113:766–72. [10] Zeitvogel J, Werfel T, Wittmann M. Keratinocytes enriched for epidermal stem cells differ in their response to IFN-gamma from other proliferative keratinocytes. Exp Dermatol 2008. [11] Companjen AR, van der Velden VH, Vooys A, Debets R, Benner R, Prens EP. Human keratinocytes are major producers of IL-18: predominant expression of the unprocessed form. Eur Cytokine Netw 2000;11:383–90.
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[12] Lebre MC, Antons JC, Kalinski P, Schuitemaker JH, van Capel TM, Kapsenberg ML, et al. Double-stranded RNA-exposed human keratinocytes promote Th1 responses by inducing a Type-1 polarized phenotype in dendritic cells: role of keratinocytederived tumor necrosis factor alpha, type I interferons, and interleukin-18. J Invest Dermatol 2003;120:990–7. [13] Ohta Y, Hamada Y, Katsuoka K. Expression of IL-18 in psoriasis. Arch Dermatol Res 2001;293:334–42. [14] Novak N, Valenta R, Bohle B, Laffer S, Haberstok J, Kraft S, et al. FcepsilonRI engagement of Langerhans cell-like dendritic cells and inflammatory dendritic epidermal cell-like dendritic cells induces chemotactic signals and different T-cell phenotypes in vitro. J Allergy Clin Immunol 2004;113:949–57. [15] Cumberbatch M, Dearman RJ, Antonopoulos C, Groves RW, Kimber I. Interleukin (IL)-18 induces Langerhans cell migration by a tumour necrosis factor-alpha- and IL-1beta-dependent mechanism. Immunology 2001;102:323–30. [16] Gutzmer R, Langer K, Mommert S, Wittmann M, Kapp A, Werfel T. Human dendritic cells express the IL-18R and are chemoattracted to IL-18. J Immunol 2003;171:6363–71. [17] Nylander-Lundqvist E, Egelrud T. Formation of active IL-1 beta from pro-IL-1 beta catalyzed by stratum corneum chymotryptic enzyme in vitro. Acta Derm Venereol 1997;77:203–6. [18] Omoto Y, Tokime K, Yamanaka K, Habe K, Morioka T, Kurokawa I, et al. Human mast cell chymase cleaves pro-IL-18 and generates a novel and biologically active IL-18 fragment. J Immunol 2006;177:8315–9. [19] Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 2004;430:213–8. [20] Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol 2003;73:213–24. [21] Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol 2001;19:423–74. [22] Yamanaka K, Clark R, Dowgiert R, Hurwitz D, Shibata M, Rich BE, et al. Expression of interleukin-18 and caspase-1 in cutaneous T-cell lymphoma. Clin Cancer Res 2006;12:376–82. [23] Kanda N, Shimizu T, Tada Y, Watanabe S. IL-18 enhances IFN-gamma-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes. Eur J Immunol 2007;37:338–50. [24] Wittmann M, Purwar R, Hartmann C, Gutzmer R, Werfel T. Human keratinocytes respond to interleukin-18: implication for the course of chronic inflammatory skin diseases. J Invest Dermatol 2005;124:1225–33. [25] Companjen A, van der Wel L, van der Fits L, Laman J, Prens E. Elevated interleukin18 protein expression in early active and progressive plaque-type psoriatic lesions. Eur Cytokine Netw 2004;15:210–6.
[26] Park HJ, Kim JE, Lee JY, Cho BK, Lee WJ, Kim T, et al. Increased expression of IL-18 in cutaneous graft-versus-host disease. Immunol Lett 2004;95:57–61. [27] Novak N, Kruse S, Potreck J, Maintz L, Jenneck C, Weidinger S, et al. Single nucleotide polymorphisms of the IL18 gene are associated with atopic eczema. J Allergy Clin Immunol 2005;115:828–33. [28] Schwarz A, Maeda A, Kernebeck K, van Steeg H, Beissert S, Schwarz T. Prevention of UV radiation-induced immunosuppression by IL-12 is dependent on DNA repair. J Exp Med 2005;201:173–9. [29] Werth VP, Bashir MM, Zhang W. IL-12 completely blocks ultraviolet-induced secretion of tumor necrosis factor alpha from cultured skin fibroblasts and keratinocytes. J Invest Dermatol 2003;120:116–22. [30] Popovic K, Ek M, Espinosa A, Padyukov L, Harris HE, Wahren-Herlenius M, et al. Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. Arthritis Rheum 2005;52:3639–45. [31] Faustin B, Reed JC. Sunburned skin activates inflammasomes. Trends Cell Biol 2008;18:4–8. [32] Gaipl US, Munoz LE, Grossmayer G, Lauber K, Franz S, Sarter K, et al. Clearance deficiency and systemic lupus erythematosus (SLE). J Autoimmun 2007;28:114–21. [33] Urbonaviciute V, Furnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med 2008;205:3007–18. [34] Muhl H, Kampfer H, Bosmann M, Frank S, Radeke H, Pfeilschifter J. Interferongamma mediates gene expression of IL-18 binding protein in nonleukocytic cells. Biochem Biophys Res Commun 2000;267:960–3. [35] Sharma S, Kulk N, Nold MF, Graf R, Kim SH, Reinhardt D, et al. The IL-1 family member 7b translocates to the nucleus and down-regulates proinflammatory cytokines. J Immunol 2008;180:5477–82. [36] Figueiredo C, Wittmann M, Wang D, Dressel R, Seltsam A, Blasczyk R, et al. Heat shock protein 70 (HSP70) induces cytotoxicity of T-helper cells. Blood 2008. [37] Franz B, Fritzsching B, Riehl A, Oberle N, Klemke CD, Sykora J, et al. Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus. Arthritis Rheum 2007;56:1910–20. [38] Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL. Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am J Pathol 2001;159:237–43.
Antiprotein S antibodies and renal cortical necrosis Renal complications are uncommon during varicella infection. In a recent paper, Larakeb et al. (Pediatric Nephrology 2009;24:207-9) reported a case of a 22-month-old boy that developed renal cortical necrosis, confirmed by kidney ultrasound and magnetic resonance imaging, ten days after varicella infection. Moreover, the serum levels of protein S was strongly reduced in association with high titers of antiprotein S antibodies. The patient recovered after glucocorticoid pulses and plasmapheresis. This study showed the rare presence of antiprotein S antibodies leading to low serum levels of the protein S and consequent renal cortical necrosis during an episode of varicella infection.
Monoarticular corticosteroid injection versus systemic administration in the treatment of rheumatoid arthritis patients: a randomized double-blind controlled study Monoarticular corticosteroid injection versus systemic administration in the treatment of rheumatoid arthritis patients is still an interest are for disccusion. Konai MS, et al. (Clin Exp Rheumatol 2009; 27: 214–21) intended to compare the efficacy and safety of intraarticular glucocorticoid injection to its systemic use for treatment of knee synovitis in rheumatoid patients. A randomized double-blind controlled study was conducted including 60 patients with RA. Patients were randomized to receive either a single intraarticular knee injection with triamcinolone hexacetonide 60 mg (3 ml) and xylocaine chloride 2% (1 ml) associated to a single intramuscular injection of 1 ml of xylocaine chloride 2% (IAI group) or 1 ml of xylocaine chloride 2% by intraarticular injection and a intramuscular injection of triamcinolone acetonide 60 mg (3 ml) and xylocaine chloride 2% (1 ml) (IM group). All patients were blindfolded for the procedure. Evaluations were performed at baseline and 1, 4, 8 and 12 weeks post-intervention. The following instruments were used: VAS for knee pain, as primary outcome, VAS for knee morning stiffness and edema; the ACR 20, 50 and 70% improvement criteria; knee circumference and goniometry; Likert's scale of improvement; daily use of oral glucocorticoid and NSAIDs, blood pressure and adverse effects. The researchers found that patients in the IAI group had significantly better results for VAS for knee pain, edema and morning stiffness as well as for improvement evaluation after intervention according to the patient (p b 0.001) and physician (p = 0.02). The results demonstrate that intraarticular injection with glucocorticoids is superior to its systemic use for the management of monoarticular synovitis in rheumatoid patients. The intraarticular approach showed better results in terms of local inflammatory variables and improvement evaluation by the patient and physician.
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
IL-18 and skin inflammation☆ Miriam Wittmann a,b,⁎, Andrew Macdonald a, Julius Renne b a b
Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK Department of Immunodermatology and Allergy Research, Hannover Medical School, Hannover, Germany
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 1 March 2009 Accepted 4 March 2009 Available online 11 March 2009
IL-18 belongs to the IL-1 family of cytokines and has recently regained interest in the context of inflammasome activation. The inflammasome dependent caspase 1 cleaves pro-IL-18 into the active form — similar to what is known for IL-1ß. Still, the action and importance of IL-18 are not completely understood. There are several indications that it plays a pathogenetically important role in chronic inflammatory conditions of epithelial organs (such as skin, gut, kidney) and importantly also in responses against self. Here, we summarise current knowledge on the role of IL-18 in human skin inflammation with a focus on its role in Cutaneous Lupus Erythematosus (CLE). There is evidence that IL-18 plays a role in CLE upstream of TNFα. In CLE but not normal keratinocytes IL-18 strongly induces TNFα release, which then results in apoptosis. Blocking TNFα in vitro prevents apoptosis of keratinocytes but anti-TNFα therapy is not applicable in LE conditions. We will discuss potential approaches to control IL-18 in skin inflammation. © 2009 Elsevier B.V. All rights reserved.
Keywords: Interleukin-18 Skin inflammation Lupus erythematosus
Contents 1. IL-18: an overview . . . . . . . . . 2. Interleukin-18 in skin inflammation 3. Autoimmune inflammatory diseases 4. Targets for therapy . . . . . . . . . Take-home . messages . . . . . . . . . . References . . . . . . . . . . . . . . .
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1. IL-18: an overview IL-18 belongs to the IL-1 family of cytokines, which has recently been re-named due to the addition of new family members (for review: [1]) and now consists of IL-1F1 to IL-1F11. The powerful proinflammatory IL-1 family members, in particular IL-1ß (IL-1F1) and IL18 (IL-1F4) are known to be tightly controlled and are synthesised as inactive precursors. Next to IL-1ß and IL-18, the recently described IL-1 family members – IL-33 (IL-1F11) and IL-1F7 – have been reported to also be cleaved by caspase 1 into biologically active cytokines. This enzyme is part of the so called “inflammasome”, a macromolecular complex formed within the cytoplasm of the cell. Intracellular nucleotide binding oligomerisation domain-like receptor (NLR)
☆ This work was supported by DFG grant Wi-1822/5-1. ⁎ Corresponding author. University of Leeds, Faculty of Biological Sciences Institute of Molecular and Cellular Biology Leeds, LS2 9JT, UK. Tel.: +44 113 343 3101; fax: +44 113 343 3046. E-mail address: [email protected] (M. Wittmann). 1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2009.03.003
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ligands activate caspases through the assembly of inflammasomes and recent reports have shown that all of the essential inflammasome components are expressed in human primary keratinocytes [2–4] — the cells which form the outermost skin layer. NLRs not only sense pathogens but also tissue injury, metabolic stress or “endogenous danger” (danger-associated molecular patterns — DAMPs). In contrast to the assembly of IL-1ß, which is controlled by two signals (induction of mRNA by Toll-like receptor complexes plus inflammasome activation), pro-IL18 is constitutively expressed and therefore only caspase 1 activation is needed to produce mature IL-18. Watanabe et al. [5] demonstrated that epidermal activation of the inflammasome by DAMPs influences the reaction towards simultaneously presented allergens enabling a switch between sensitisation and tolerance induction. As a consequence IL-18 is likely to be an important factor in the initiation of inflammation and autoimmune disorders [6]. In skin immunopathophysiology keratinocytes play a prominent role as effective producers of antimicrobial defensins, chemokines and cytokines [7,8]. IL-18 is produced by keratinocytes [9–12] and in addition Langerhans cells (LC) located in the epidermis [13] and
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Fig. 1. A. Histopathological features of CLE include prominent changes at the dermoepidermal interface such as hydropic degeneration of the basal epithelial layer. Apoptotic keratinocytes in the epidermis may be numerous. In addition, the lymphocytic infiltration (here: CD8 T cells are stained in red) is confined to the upper dermis and often appears band-like. Hyperkeratosis and follicular plugging is mainly seen in chronic discoid forms of LE. B. Immunopathogenesis: In CLE apoptotic keratinocytes are found mainly in the basal layer of the epidermis. Altered IL-18 sensitivity with high IL-18R expression on keratinocytes seems characteristic for CLE. IL-18 – which is expressed in the epidermis of skin lesions – induces epidermal production of the chemokine CXCL10 which favours the attraction of IFNγ producing lymphocytes. T cells accumulate near the dermoepidermal border in close vicinity to keratinocytes. Furthermore, IL-18 results in the release of TNFα from activated keratinocytes. TNFα acts in an autocrine feedback loop to induce apoptosis in neighbouring epidermal cells. Due to a clearance deficiency in lupus conditions, apoptotic cells are not removed, undergo “secondary necrosis” and as a consequence may release danger associated molecular patterns (DAMPs) such as HMGB1 or HSPs into the extracellular space. When immunocompetent cells encounter (formerly intracellular auto-)antigens in the context of DAMPs they may switch from a tolerant (normally induced by apoptotic cells) toward an auto-immune response/or cytotoxicity [36], which may also be favoured by the absence of Treg cells in CLE skin lesions [37]. DAMPs may also contribute to further activate keratinocytes to express chemokines and cytokines thus sustaining local inflammation. A chemotactic activity of IL-18 on DC [15] may also contribute to the accumulation of plasmacytoid Dendritic Cells (pDC) in the upper dermis. pDC have been found in CLE [38] and are known producers of type I IFNs which in turn activate keratinocytes to, amongst others, express IL-18R on their surface [23]. Due to the presence of inflammatory mediators the integrity of the basement membrane is destroyed facilitating influx of inflammatory cells.
dermal dendritic cells (DC) in the skin are also able to produce mature IL-18 in response to inflammatory stimulation, which in turn contributes to the regulation of LC/DC migration [14,15]. Although inflammasome components are expressed in human kerationcytes [2] and the presence of bioactive IL-1ß and IL-18 in the supernatant of activated keratinocytes has clearly been shown [2,9], it is still not clear how exactly these molecules are activated by epithelial cells. Cleavage of the pro-IL-1ß/pro-IL-18 by intracellular caspase 1 has not been demonstrated in keratinocytes. Although an extracellular cleavage by mast cell chymase or chymotryptic epidermal enzymes [16,17] and the release of inflammasome components including caspase 1 has been shown for keratinocytes and other cells [2,18], the processes involved in the generation of epidermal mature IL-1ß and IL-18 remain to be fully elucidated. Certainly, epithelial cells may not produce mature IL18 under steady-state-conditions but rather in an activated state as seen in the context of inflammation. IL-18 plays an important pro-inflammatory role [19] and is involved in the induction of inflammatory mediators as well as regulation of the cytotoxic activity of Natural Killer (NK) cells and T cells. Furthermore, IL-18 was found to support the differentiation and activation of different T helper (Th) cell subsets depending on the surrounding cytokine profile [20]. For example, in the presence of IL12 a Th1 response is favoured (e.g. in chronic eczema or psoriatic skin inflammation), in its absence a Th2 response may be enhanced, such as seen in cutaneous T cell lymphoma associated skin inflammation [21] or acute eczema. Therefore IL-18, together with its activation by the inflammasome, bridges the innate and adaptive immune responses [1]. Keratinocytes can directly respond to IL-18 [22,23]. The IL-18R needs two signals to be upregulated in keratinocytes from healthy patients [23], one of which has to be an interferon (IFN) and possible second signals include TNFα or dsRNA. Keratinocytes respond to IL-18 with the production of CXCL10, a chemokine that mainly attracts IFNγ producing, CXCR3 positive Th1 cells [22,23]. Furthermore, IL-18 can up-regulate the expression of MHC class II molecules on keratinocytes [23], which may have an important role in situations where the skin is infected with superantigen producing staphylococcus aureus. In the presence of superantigen MHC class II positive keratinocytes can
further enhance IFNγ production by lymphocytes with the appropriate Vß chain. 2. Interleukin-18 in skin inflammation IL-18 expression and effector functions have been described in inflammatory diseases across a broad range of tissues (reviewed in [19]) including joints [24], kidney [25] and the skin. Immunohistology and RT-PCR analysis demonstrate higher levels of expression of both IL-18 and IL-18R in lesional skin, including cutaneous lupus erythematosus (CLE), psoriasis, GvHD, cutaneous T cell lymphoma and atopic dermatitis (AD) compared to healthy skin [4,12,21,23,26]. However, a drawback of these studies is that the methodical approaches were based on either PCR or immunohistology, which do not distinguish between pro-IL-18 and mature IL-18. AD, one of the most prevalent skin diseases today could be linked to polymorphisms of the IL-18 gene [27]. In murine AD models IL-18 seems to play an important role in acute eczema but data for the skin compartment in human acute AD are lacking. As for the chronic phase of eczema, predominated by IFNγ, we were able to show that autologous T cells produced IFNγ in the presence of IL-18 stimulated keratinocytes and SEB [23]. 3. Autoimmune inflammatory diseases A number of studies point to the relevance of IL-18 in lupus pathology (for review: [6]), as well as other autoimmune inflammatory diseases. Our data, comparing IL-18 expression in lesional skin of CLE to acute AD point to high IL-18 expression levels in CLE skin lesions. Keratinocytes from patients with CLE show a proinflammatory response pattern distinct from normal keratinocytes in which IL-18 seems to play a significant role Fig. 1. In CLE keratinocytes IL-18R is easily upregulated in the presence of only one signal. IFNγ as well as TNFα alone is able to further up-regulate IL-18R, which already shows a higher basal expression in CLE keratinocytes compared to healthy donors. The underlying reason for high basal IL-18R expression is not clear to date. Nevertheless, the effect of IL-18 on CLE keratinocytes is high production of TNFα and induction of apoptosis which is not seen
M. Wittmann et al. / Autoimmunity Reviews 9 (2009) 45–48
in healthy keratinocytes. We were able to show that IL-18 dependent apoptosis was mediated by autocrine TNFα and diminished IL-12 expression — the latter has been shown previously to protect keratinocytes from TNFα or UV mediated apoptosis [28,29]. Overexpression of TNFα has been recognised for LE skin lesions [30]. In accordance with previous reports on CLE [30], we could not find a link to the known TNF-308 promoter polymorphism. However, in both studies mentioned, the number of patients included was low. An unanswered question is whether the high IL-18 susceptibility and high TNFα production is a genetic or epigenetic feature of epithelial cells. Of note, we cultured our keratinocytes from epidermal stem cells of the hair follicle, thus these cells were derived from non-lesional skin of LE patients. Subclinical involvement of the scalp region is however possible as many of the patients included in the study are highly UV sensitive and UV light is a known trigger factor of LE. Of note, UV has been recognised as an inducer of the inflammasome [2,31]. The cells maintained their phenotype with high IL-18R expression and TNFα production also after repeated thawing and re-culture cycles. Taken together, in CLE IL-18 may occupy a proximal position in the proinflammatory cytokine cascade. So far, we do not know whether the increased TNFα production upon IL-18 stimulation in CLE keratinocytes is due to increased IL-18 sensitivity or altered TNFα regulation. It has been proposed that IL-18 itself may play a role in the establishment of (auto)-reactivity. In lupus conditions the noninflammatory clearance of apoptotic cells is impaired [32] and it has been proposed that the increased rate of apoptosis increases the chance of leakage of intracellular antigens. A number of studies indicate that DAMPs such as high-mobility group box-1 (HMGB1) [33], ATP and heat shock protein 70 (HSP70) may be released from intracellular compartments. Encounter of both an intracellular antigen and a DAMP (which activates the inflammasome and leads to caspase 1 dependent release of mature IL-18 and IL-1ß) by immunocompetent cells may trigger an autoimmune response. It remains to be shown whether autoimmune phenomena also described for AD and psoriasis are linked to inflammasome activation and the presence of IL-18 in the tissue. Another hint for IL-18 playing an important and potentially harmful role in inflammatory disorders of the skin is the fact that freshly isolated and IFNγ stimulated epidermal stem cells seem to have switched off the capacity to express IL-18 while still expressing CXCL10 and other cytokines [10]. These studies have however been performed outside the stem cell niche and the cells underwent only limited purification by adherence to integrin ß1 ligands. It remains to be determined whether absence of IL-18 is important for the so-called protected stem cell niche. Thus far, we lack the appropriate experimental systems to analyse in detail the hierarchy of mediators in human inflammatory conditions. Unfortunately, disease models in rodents often fail to depict the human situation and many of the most important immunoregulatory mediators are fundamentally different between mice and men. As outlined in greater detail by Faustin and Reed [31], there are important differences between the two species with respect to NLR-family proteins and inflammasome associated cytokines. For example human but not murine keratinocytes produce pro-IL-1ß.
4. Targets for therapy For LE pathology, it is not clear to date, if epithelial cells release the IL-18 counter-regulating molecules IL-18BP and IL-1F7. Also, IL-33 which favours Th2 mediated responses could potentially be of benefit if upregulated in LE pathology. Furthermore, the source of epidermal IL-1 and IL-18 and their activation remain to be clearly deciphered. Importantly, the reason why CLE keratinocytes react to IL-18 with high TNFα release is unknown. We need to understand these issues in CLE
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pathology in order to understand the contribution of tissue resident cells to immunopathology and to identify therapeutic targets. With the data available to date, targeting IL-18 bioactivity may be a promising therapeutic intervention in CLE conditions. It has become clear that targeting TNFα by anti-TNFα therapy exacerbates (or induces) LE conditions with increases seen in serum anti-dsDNA autoantibodies. Therefore, IL-18 might be a better target in the epidermis as it may only abrogate autocrine TNFα release, thus reducing the apoptotis rate of keratinocytes. An interesting molecule in this context is IL-18 binding protein (IL-BP), an endogenous antagonist with high neutralising capacity for IL-18. IL-18BP binds to mature IL-18, but not pro-IL-18, with high affinity and prevents its interaction with cell surface receptors [1]. In healthy human epithelial cells, IFNγ is known to induce the release of IL-18BP [34]. In some autoimmune diseases an IL-18/IL-18BP imbalance has been described. Data for LE conditions are lacking so far. Of note is the fact that another IL-1 family member, IL-1F7, has been demonstrated to enhance the inhibitory effect of IL-18BP and recent data in the murine system suggest that it may also act as a transcriptional modulator reducing IL6, TNFα and IL-1α [35]. Another target may be caspase 3 which cleaves IL-18 into inactive forms. It may be argued that previous attempts with caspase-1 inhibitors have not been terribly successful in pre-clinical trials for connective tissue diseases. This could be due to the fact that other enzymes are able to cleave pro-IL-18 and also that other IL-1 family members, with potentially antagonistic action, are also cleaved by caspase 1 (IL-1F7, IL-33). This points to the fact that inflammasome inhibitors may also fail to show beneficial effects with regard to IL-18 counter-regulation but this remains to be shown. Take-home messages • IL-18 is found in chronic inflammatory skin conditions • It is still unclear how pro-IL-18 is activated in the epidermis • Keratinocytes from Cutaneous Lupus Erythematosus (CLE) patients overexpress IL-18R • In CLE IL-18 may act upstream of TNFα with regard to apoptosis induction • Manipulating the balance between IL-18 and its endogenous antagonists IL-18BP / IL-1F7 may be a promising therapeutic approach in lupus conditions References [1] Arend WP, Palmer G, Gabay C. IL-1, IL-18, and IL-33 families of cytokines. Immunol Rev 2008;223:20–38. [2] Feldmeyer L, Keller M, Niklaus G, Hohl D, Werner S, Beer HD. The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes. Curr Biol 2007;17:1140–5. [3] Harder J, Nunez G. Functional Expression of the Intracellular Pattern Recognition Receptor NOD1 in Human Keratinocytes. J Invest Dermatol 2009 [Electronic publication ahead of print]. [4] Wang D, Drenker M, Eiz-Vesper B, Werfel T, Wittmann M. Evidence for a pathogenetic role of interleukin-18 in cutaneous lupus erythematosus. Arthritis Rheum 2008;58:3205–15. [5] Watanabe H, Gehrke S, Contassot E, Roques S, Tschopp J, Friedmann PS, et al. Danger signaling through the inflammasome acts as a master switch between tolerance and sensitization. J Immunol 2008;180:5826–32. [6] Boraschi D, Dinarello CA. IL-18 in autoimmunity: review. Eur Cytokine Netw 2006;17:224–52. [7] Albanesi C, Scarponi C, Giustizieri ML, Girolomoni G. Keratinocytes in inflammatory skin diseases. Curr Drug Targets Inflamm Allergy 2005;4:329–34. [8] Wittmann M, Werfel T. Interaction of keratinocytes with infiltrating lymphocytes in allergic eczematous skin diseases. Curr Opin Allergy Clin Immunol 2006;6:329–34. [9] Naik SM, Cannon G, Burbach GJ, Singh SR, Swerlick RA, Wilcox JN, et al. Human keratinocytes constitutively express interleukin-18 and secrete biologically active interleukin-18 after treatment with pro-inflammatory mediators and dinitrochlorobenzene. J Invest Dermatol 1999;113:766–72. [10] Zeitvogel J, Werfel T, Wittmann M. Keratinocytes enriched for epidermal stem cells differ in their response to IFN-gamma from other proliferative keratinocytes. Exp Dermatol 2008. [11] Companjen AR, van der Velden VH, Vooys A, Debets R, Benner R, Prens EP. Human keratinocytes are major producers of IL-18: predominant expression of the unprocessed form. Eur Cytokine Netw 2000;11:383–90.
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[12] Lebre MC, Antons JC, Kalinski P, Schuitemaker JH, van Capel TM, Kapsenberg ML, et al. Double-stranded RNA-exposed human keratinocytes promote Th1 responses by inducing a Type-1 polarized phenotype in dendritic cells: role of keratinocytederived tumor necrosis factor alpha, type I interferons, and interleukin-18. J Invest Dermatol 2003;120:990–7. [13] Ohta Y, Hamada Y, Katsuoka K. Expression of IL-18 in psoriasis. Arch Dermatol Res 2001;293:334–42. [14] Novak N, Valenta R, Bohle B, Laffer S, Haberstok J, Kraft S, et al. FcepsilonRI engagement of Langerhans cell-like dendritic cells and inflammatory dendritic epidermal cell-like dendritic cells induces chemotactic signals and different T-cell phenotypes in vitro. J Allergy Clin Immunol 2004;113:949–57. [15] Cumberbatch M, Dearman RJ, Antonopoulos C, Groves RW, Kimber I. Interleukin (IL)-18 induces Langerhans cell migration by a tumour necrosis factor-alpha- and IL-1beta-dependent mechanism. Immunology 2001;102:323–30. [16] Gutzmer R, Langer K, Mommert S, Wittmann M, Kapp A, Werfel T. Human dendritic cells express the IL-18R and are chemoattracted to IL-18. J Immunol 2003;171:6363–71. [17] Nylander-Lundqvist E, Egelrud T. Formation of active IL-1 beta from pro-IL-1 beta catalyzed by stratum corneum chymotryptic enzyme in vitro. Acta Derm Venereol 1997;77:203–6. [18] Omoto Y, Tokime K, Yamanaka K, Habe K, Morioka T, Kurokawa I, et al. Human mast cell chymase cleaves pro-IL-18 and generates a novel and biologically active IL-18 fragment. J Immunol 2006;177:8315–9. [19] Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 2004;430:213–8. [20] Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol 2003;73:213–24. [21] Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol 2001;19:423–74. [22] Yamanaka K, Clark R, Dowgiert R, Hurwitz D, Shibata M, Rich BE, et al. Expression of interleukin-18 and caspase-1 in cutaneous T-cell lymphoma. Clin Cancer Res 2006;12:376–82. [23] Kanda N, Shimizu T, Tada Y, Watanabe S. IL-18 enhances IFN-gamma-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes. Eur J Immunol 2007;37:338–50. [24] Wittmann M, Purwar R, Hartmann C, Gutzmer R, Werfel T. Human keratinocytes respond to interleukin-18: implication for the course of chronic inflammatory skin diseases. J Invest Dermatol 2005;124:1225–33. [25] Companjen A, van der Wel L, van der Fits L, Laman J, Prens E. Elevated interleukin18 protein expression in early active and progressive plaque-type psoriatic lesions. Eur Cytokine Netw 2004;15:210–6.
[26] Park HJ, Kim JE, Lee JY, Cho BK, Lee WJ, Kim T, et al. Increased expression of IL-18 in cutaneous graft-versus-host disease. Immunol Lett 2004;95:57–61. [27] Novak N, Kruse S, Potreck J, Maintz L, Jenneck C, Weidinger S, et al. Single nucleotide polymorphisms of the IL18 gene are associated with atopic eczema. J Allergy Clin Immunol 2005;115:828–33. [28] Schwarz A, Maeda A, Kernebeck K, van Steeg H, Beissert S, Schwarz T. Prevention of UV radiation-induced immunosuppression by IL-12 is dependent on DNA repair. J Exp Med 2005;201:173–9. [29] Werth VP, Bashir MM, Zhang W. IL-12 completely blocks ultraviolet-induced secretion of tumor necrosis factor alpha from cultured skin fibroblasts and keratinocytes. J Invest Dermatol 2003;120:116–22. [30] Popovic K, Ek M, Espinosa A, Padyukov L, Harris HE, Wahren-Herlenius M, et al. Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. Arthritis Rheum 2005;52:3639–45. [31] Faustin B, Reed JC. Sunburned skin activates inflammasomes. Trends Cell Biol 2008;18:4–8. [32] Gaipl US, Munoz LE, Grossmayer G, Lauber K, Franz S, Sarter K, et al. Clearance deficiency and systemic lupus erythematosus (SLE). J Autoimmun 2007;28:114–21. [33] Urbonaviciute V, Furnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med 2008;205:3007–18. [34] Muhl H, Kampfer H, Bosmann M, Frank S, Radeke H, Pfeilschifter J. Interferongamma mediates gene expression of IL-18 binding protein in nonleukocytic cells. Biochem Biophys Res Commun 2000;267:960–3. [35] Sharma S, Kulk N, Nold MF, Graf R, Kim SH, Reinhardt D, et al. The IL-1 family member 7b translocates to the nucleus and down-regulates proinflammatory cytokines. J Immunol 2008;180:5477–82. [36] Figueiredo C, Wittmann M, Wang D, Dressel R, Seltsam A, Blasczyk R, et al. Heat shock protein 70 (HSP70) induces cytotoxicity of T-helper cells. Blood 2008. [37] Franz B, Fritzsching B, Riehl A, Oberle N, Klemke CD, Sykora J, et al. Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus. Arthritis Rheum 2007;56:1910–20. [38] Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL. Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am J Pathol 2001;159:237–43.
Antiprotein S antibodies and renal cortical necrosis Renal complications are uncommon during varicella infection. In a recent paper, Larakeb et al. (Pediatric Nephrology 2009;24:207-9) reported a case of a 22-month-old boy that developed renal cortical necrosis, confirmed by kidney ultrasound and magnetic resonance imaging, ten days after varicella infection. Moreover, the serum levels of protein S was strongly reduced in association with high titers of antiprotein S antibodies. The patient recovered after glucocorticoid pulses and plasmapheresis. This study showed the rare presence of antiprotein S antibodies leading to low serum levels of the protein S and consequent renal cortical necrosis during an episode of varicella infection.
Monoarticular corticosteroid injection versus systemic administration in the treatment of rheumatoid arthritis patients: a randomized double-blind controlled study Monoarticular corticosteroid injection versus systemic administration in the treatment of rheumatoid arthritis patients is still an interest are for disccusion. Konai MS, et al. (Clin Exp Rheumatol 2009; 27: 214–21) intended to compare the efficacy and safety of intraarticular glucocorticoid injection to its systemic use for treatment of knee synovitis in rheumatoid patients. A randomized double-blind controlled study was conducted including 60 patients with RA. Patients were randomized to receive either a single intraarticular knee injection with triamcinolone hexacetonide 60 mg (3 ml) and xylocaine chloride 2% (1 ml) associated to a single intramuscular injection of 1 ml of xylocaine chloride 2% (IAI group) or 1 ml of xylocaine chloride 2% by intraarticular injection and a intramuscular injection of triamcinolone acetonide 60 mg (3 ml) and xylocaine chloride 2% (1 ml) (IM group). All patients were blindfolded for the procedure. Evaluations were performed at baseline and 1, 4, 8 and 12 weeks post-intervention. The following instruments were used: VAS for knee pain, as primary outcome, VAS for knee morning stiffness and edema; the ACR 20, 50 and 70% improvement criteria; knee circumference and goniometry; Likert's scale of improvement; daily use of oral glucocorticoid and NSAIDs, blood pressure and adverse effects. The researchers found that patients in the IAI group had significantly better results for VAS for knee pain, edema and morning stiffness as well as for improvement evaluation after intervention according to the patient (p b 0.001) and physician (p = 0.02). The results demonstrate that intraarticular injection with glucocorticoids is superior to its systemic use for the management of monoarticular synovitis in rheumatoid patients. The intraarticular approach showed better results in terms of local inflammatory variables and improvement evaluation by the patient and physician.