Interleukin-18 and stress

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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v

Review

Interleukin-18 and stress Shuei Sugama a,⁎, Bruno Conti b,⁎ a

Department of Physiology, Nippon Medical School, 1-1-5 Sendagi Bunkyo-ku, Tokyo 113-8602, Japan Harold L. Dorris Neurological Research Center, Molecular and Integrative Neurosciences Department, The Scripps Research Institute, CA 92037, USA

b

A R T I C LE I N FO

AB S T R A C T

Article history:

Interleukin-18 (IL-18) is a pro-inflammatory cytokine believed to play a role in a variety of

Accepted 16 November 2007

conditions and diseases including infections, autoimmunity, cancer, diabetes and

Available online 28 November 2007

atherosclerosis. IL-18 is also a possible contributor to the sickness syndrome by inducing anorexia and sleep. Originally recognized to be produced by cells of the immune system, IL-

Keywords:

18 is also found in endocrine tissues, including the adrenal and the pituitary glands, and in

IL-18

the central nervous system where it is produced by microglial and ependymal cells as well

Stress

as by neurons of the medial habenular nucleus. IL-18 is produced constitutively and its

Neuroimmunomodulation

levels can increase during infection but also during stress in the absence of an exogenous stimulus. IL-18 levels are elevated by activation of the hypothalamic–pituitary–adrenal (HPA) axis in a tissue specific way via differential promoter and splicing usage, and may be down-regulated by the activation of the para-sympathetic system. This suggested the possibility that IL-18 may participate in the regulation of the HPA axis or that it may have a role in mediating the CNS dependent effects on the susceptibility to or the progression of diseases. This review summarizes the evidence linking stress and IL-18 and discusses the possible implication of the neuro-immuno-modulatory action of IL-18. © 2008 Published by Elsevier B.V.

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

9.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IL-18 receptor signaling and IL-18 binding protein . . . . . . . . . . . . . . . . . . . . . . . . . . Tissue specific elevation of IL-18 synthesis during stress or neurogenic stimulation . . . . . . . . Stress-dependent modulation of IL-18 is achieved by tissue specific promoter usage and splicing Maturation of IL-18 during stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Glucocorticoids, IL-18 and HPA axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parasympathetic down-regulation of IL-18 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological roles of IL-18 and clinical relevance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Peripheral action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Central action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Association of IL-18 with psychiatric disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . .

⁎ Corresponding authors. E-mail addresses: [email protected] (S. Sugama), [email protected] (B. Conti). 0165-0173/$ – see front matter © 2008 Published by Elsevier B.V. doi:10.1016/j.brainresrev.2007.11.003

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10. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.

Introduction

The hypothesis that emotions can influence the susceptibility to and the progression of diseases is generally accepted and supported by clinical evidence. Nevertheless, the mechanisms and the molecules that modulate this phenomenon remain difficult to investigate. Limitations include the methodological and experimental difficulties in approaching a pluridisciplinary field that often involves the interaction between two or more systems, the intrinsic homeostatic nature of several mechanisms at play, and the identification of its molecular mediators. Among the most interesting candidates are the mechanisms and molecules mediating the interactions between the nervous and the immune systems, often via the endocrine system and thus referred to as neuro-immunomodulators or neuro-endocrine-immunomodulators (for comprehensive reviews see Ader, 2006). These include molecules of the hypothalamic–pituitary–adrenal (HPA) axis such as adrenocorticotropic hormones (ACTH) and glucocorticoids (GC) but also neurotransmitters like acetylcholine, epinephrine and norepinephrine. These molecules are produced and/or released when emotions or psychological stress triggers the activation of the HPA axis or of the sympathetic nervous system (Kventnansky et al., 1977; Sabban and Kventnansky, 2001; Turnbull and Rivier, 1999). HPA axis activation occurs when stress or other stimuli induce the production of corticotropic releasing hormone (CRH) in the parvocellular neurons of the paraventricular nucleus of the hypothalamus. Consequently, CRH stimulates the anterior pituitary gland to produce and secrete ACTH. Subsequently, ACTH stimulates the cells of the adrenal cortex to produce and release GC. These steroids inhibit the synthesis and secretion of CRH within the hypothalamus and POMC-derived peptides in the pituitary (Keller-Wood and Daliman, 1984; Young et al., 1986; Turnbull and Rivier, 1999). The amplitude and the duration of the pituitary–adrenal response can also be modulated through the hippocampus, which express receptors for circulating GC, and is known to inhibit the hypothalamus via neuronal bed nucleus in the stria terminalis and the preoptic area (Jacobson and Sapolsky, 1991; McEwen, 1999). A place in this scenario may be occupied by interleukin 18 (IL-18), a cytokine primarily recognized to be a modulator of immune functions and whose synthesis can be modulated by neurogenic stimulation or stress. IL-18 was originally isolated as an interferon-gamma (IFN-γ) inducing factor (IGIF) from Kupffer cells of mice injected with Propionibacterium acnes and lipopolysaccharides (LPS) (Okamura et al., 1995). Studies on the biological activity of IL-18 have demonstrated that this molecule has pro-inflammatory, pro-apoptotic, pro-atherogenic activities and plays a role in several diseases including diabetes, atherosclerosis, ischemic heart diseases, infection and cancer (Dinarello and Fantuzzi, 2003; Dinarello, 2006a; Golab, 2000; Reddy, 2004; Stuyt et al., 2002). The distribution

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and expression profile of IL-18 allow the production of this molecule to take place in the absence of a microbial challenge in a tissue specific manner through differential usage of its promoter. IL-18 is constitutively expressed in the same adrenal cortical cells that produce glucocorticoids and in the pituitary gland (Conti et al., 1997, 2000; Conti, 2000; Sekiyama et al., 2006; Sugama et al., 2000). In the CNS, IL-18 was also found in the pituitary gland, ependymal cells and the neurons of the medial habenula where its synthesis was elevated by stress (Conti et al., 1997; Nagai et al., 2005, 2006; Sugama et al., 2002; Wang et al., 2006). These results suggest that IL-18 may be a signal mediating the communication between the nervous, the endocrine and the immune systems. Although the possibility that IL-18 may be a regulator of the HPA axis will be discussed, the focus of this review is to summarize evidence suggesting that IL-18 may be a modulator of biological functions during stress. The action of IL-18 in the central nervous system was recently reviewed with special emphasis on the role of this cytokine with respect to local inflammation and neuronal damage (Felderhoff-Mueser et al., 2005). We will also discuss the implications that stressdependent IL-18 may have some effects on diseases.

2. IL-18 receptor signaling and IL-18 binding protein The IL-18 receptor complex (IL-18R) is a member of the IL-1/ Toll like receptor superfamily. The receptor is composed of interleukin 1 receptor related protein (IL-1RrP, IL-18Rα or IL-1R5) to which IL-18 binds (Torigoe et al., 1997) and of IL-18 accessory protein (IL-18RAcP, IL-18Rβ or IL-1R7) which initiates signal transduction. Binding of IL-18 to IL-18R recruits the IL-1 receptor-activating kinase (IRAK) via the adapter protein MyD88 (Adachi et al., 1998; Kojima et al., 1998; Robinson et al., 1997). IRAK then autophosphorylates and dissociates from the receptor complex, subsequently interacting with TNFR-associated factor-6 (TRAF6), which relays the signal via NF-κBinduced kinase (NIK) to two IκB kinases (IKK-1 and IKK-2). This leads to the formation of the activated p65 homodimer or p65/ p50 heterodimer forms of NF-κB (Adachi et al., 1998; Matsumoto et al., 1997; Robinson et al., 1997). Engagement of the IL-18R complex also activates the mitogen-activated protein kinase (MAPK) p38, JNK and ERK through both IRAK and STAT3 (Kalina et al., 2000; Netea et al., 2006; Tomura et al., 1998; Tsutsui et al., 1996). Whether IL-18 also signals through the recently discovered non-Myd88 Toll signaling pathways is not yet clear. IL-18R has been demonstrated in several tissues including spleen, lung, liver, heart, intestine and the brain (Sergi and Penttila, 2004). Its possible modulation during stress remains to be investigated. The action of IL-18 can be inhibited upon binding to the IL-18 binding protein (IL-18BP), a member of the immunoglobulin

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superfamily that was purified from human urine and mouse serum (Aizawa et al., 1999; Novick et al., 1999). Four isoforms of human IL-18BP have been found (IL-18BPa, b, c and d) (Kim et al., 2000a). Only IL-18BPa and c strongly inhibit IL-18 action. Two mouse isoforms of IL-18BP, perhaps orthologs of human IL-18BPa and c, have been described and also attenuate IL-18 action (Kim et al., 2000a; Meyer Zum Buschenfelde et al., 1997). Similarly to the IL-18R, the modulation of IL-18BP during stress remains to be assessed.

3. Tissue specific elevation of IL-18 synthesis during stress or neurogenic stimulation IL-18 has been found in a wide range of antigen-presenting immune cells including monocytes/macrophages, Kupffer cells, T and B cells, osteoblasts, dendritic cells as well as in the endocrine adrenal and the pituitary glands (de Saint-Vis et al., 1998; Okamura et al., 1995; Takeuchi et al., 1997; Udagawa et al., 1997). Constitutive expression of IL-18 was demonstrated in the cells of the zona fasciculata and the

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zona reticularis of the adrenal cortex, the same that produce glucocorticoids (Conti et al., 1997; Sugama et al., 2000). In these cells, the expression of IL-18 mRNA and protein was elevated by cold and/or restraint stress, and following reserpineinduced catecholamine depletion, suggesting the possibility that in these organs IL-18 could be produced following the activation of the hypothalamic–pituitary–adrenal (HPA) axis. This hypothesis was eventually supported by demonstration that the adrenal gland synthesized IL-18 in response to ACTH (Conti et al., 1997, 2000; Sekiyama et al., 2005, 2006; Sugama et al., 2000, 2006). Interestingly, ACTH induced IL-18 mRNA in the adrenal gland, but not in cells of the immune systems of the spleen or the gut associated lymphoid tissue (GALT) of the lamina propria of the duodenum (Sugama et al., 2000). Although the synthesis of IL-18 in the adrenal gland following infection remains to be assessed, it was recently demonstrated that immobilization stress increased adrenal and plasma IL-18 levels and that the elevation of plasma IL-18 levels was decreased by adrenalectomy, hemi-adrenalectomy or by blocking ACTH action (Sekiyama et al., 2005, Sugama et al., 2006). Stress induced transient IL-18 elevation in

Fig. 1 – Schematic representation of the existence of two distinct pathways for the stimulation of IL-18 synthesis. The induction of IL-18 occurs through infection/inflammation (immunological pathway) in cells of the immune system and during stress (endocrinological pathway) via the activation of the hypothalamic–pituitary–adrenal (HPA) axis after release of corticotropic releasing hormone (CRH) and of the adrenocorticotropic hormone (ACTH). The primary target cells, the biological action of IL-18 and the immune system and its relevance with specific diseases are indicated (see text for details).

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corticotrope cells of the anterior lobe of the pituitary gland where increase of IL-18 mRNA level was observed also after adrenalectomy (Wang et al., 2006). In the brain IL-18 is expressed in microglia, in the ependymal cells and in the neurons of the medial habenula where its synthesis was also elevated by restraint stress (Conti et al., 1999; Culhane et al., 1998; Prinz and Hanisch, 1999; Sugama et al., 2002). The habenula is composed of one medial nucleus (MHb) and two lateral nuclei (LHb) with distinct neuronal connections and it is known to be involved in a wide variety of biological functions, including olfaction, ingestion, mating, endocrine functions, sleep, wake mechanisms, pain and analgesia, motor behavior, learning processes, and stress response (Andres et al., 1999; Ellison, 1994; Sandyk, 1991; Sutherland, 1982). The LHb extends fibers to the lateral subnucleus of the interpeduncular (IP) nucleus, also known as the IP pathway, a region reported to modulate the levels of circulating adrenal hormones (Murray et al., 1994). It has been hypothesized that the habenula may be a site for the interaction of neuro-endocrine and immune functions (Silver et al., 1996). Thus, IL-18 might mediate the communication between the CNS and the periphery, modulating neuro-endocrine functions but its actual role in the habenula remains to be determined.

4. Stress-dependent modulation of IL-18 is achieved by tissue specific promoter usage and splicing Experiments in rats demonstrated that IL-18 was synthesized in a tissue- and stimulus-specific fashion and suggested the existence of precise molecular and/or biochemical pathways for its regulation during stress (Sugama et al., 2000). The finding that the size of IL-18 mRNAs differed in endocrine and immune system cells was the first indication that such specificity could be achieved at the transcriptional level. This hypothesis was demonstrated first in the adrenal gland and subsequently in the pituitary gland by the characterization of IL-18 gene and the identification of multiple promoters found to be tissue specific (Sugama et al., 2000; Wang et al., 2006). Mouse and rat IL-18 gene were reported to have at least two TATA-less promoters upstream the two untranslated exons 1 and 2, thus referred to as promoter 1 (P1) and promoter 2 (P2) (Fig. 1) (Sugama et al., 2000; Tone et al., 1997). Putative cis-actin elements for transcription factors are found in P1 included NF-κB, AP1, PU.1, GATA-1, NF-GMb, Oct-2A, ICSbf, while P2 contained NF-κB, AP1 and PU.1 (Fig. 2). The basal and/or inducible activity of these promoters was investigated in vitro using the machrophage cell line RAW264, with contrasting results most likely due to differences in the cell lines and the experimental conditions used (Kim et al., 2000b; Sugama et al., 2000). In vivo, it was clearly shown that rat IL-18 mRNA is expressed at both basal and inducible levels exclusively from P1 in adrenal gland, from P2 in the cells of the immune system (Sugama et al., 2000), demonstrating that the IL-18 gene is organized in a fashion that allows its specific modulation following neurogenic stimulation (Fig. 2). The structure of IL-18 gene became more elaborated after analysis of the 5′ end of the IL-18 mRNA obtained from rat pituitary gland where IL-18 mRNA was induced by stress or adrenalectomy in the anterior lobe (Wang et al., 2006). Five novel untranslated putative

exons (never reported in the IL-18 mature transcripts of any other tissues investigated) were identified in addition to exon 1 and named exons 0A, 0B, 1A, 1B and 1C (Wang et al., 2006). Furthermore, three distinct splicing variants were demonstrated suggesting the possibility that differential splicing might also participate in the modulation of pituitary IL-18 synthesis during stress. In human, the structure of IL-18 promoter was not investigated extensively and the organization in 2 or multiple promoters was not demonstrated. However, the same cis-acting elements that mediate the constitutive and the inducible expression in mouse and rat were found in the 5′ region upstream exon 1 (Kalina et al., 2000).

5.

Maturation of IL-18 during stress

IL-18 transcript encodes for a 24 kDa peptide referred to as proIL-18. Pro-IL-18 is subsequently cleaved into the mature and active 18 kDa also recognized as the secretable form of IL-18. This process is mediated by the interleukin-1β-converting enzyme (ICE, caspase-1), the same enzyme that processes Interleukin 1β (Ghayur et al., 1997; Gu et al., 1997) (Fig. 2). IL-18 secretion is believed to occur at least in part by exocytosis as demonstrated in dendritic cells after antigen specific contact with T-cells, a mechanism modulated by calcium (Gardella et al., 2000). The presence of the precursor and the active forms of IL-18 in the adrenal glands suggested that IL-18 could be properly processed in this organ (Conti et al., 2000), a hypothesis further supported by finding that the level of caspase-1 in the adrenal gland increased 10-fold following stress (Sekiyama et al., 2005). The cascade of events leading to IL-18 maturation in the adrenal gland during stress was also investigated. Activation of the HPA axis generated eventually induced p38 MAPK phosphorylation (Thr180/Tyr182) promoting the maturation of caspase-11 that, in turn, activated caspase-1 (Sekiyama et al., 2006). Detection of mature IL-18 remained difficult in tissues including the adrenal gland during stress where pro-IL-18 is primarily found. This observation suggested at first that stress would only elevate the intracellular level of pro-IL-18 and that a second stimulus would be required for its maturation and secretion. Unilateral or bilateral adrenalectomy reduced the circulating levels of IL-18 demonstrating the effects of stress on the levels of circulating IL-18 (Sekiyama et al., 2006; Sugama et al., 2006). Albeit the ELISA assay utilized did not distinguish between pro-IL-18 and mature IL-18 circulating IL-18 was detected following stress (Sekiyama et al., 2006; Sugama et al., 2006). In addition, it is important to consider that extracellular maturation of pro-IL-18 has be reported to occur independent of caspase-1 via protainase-3, mast cell chymase, matrix metalloproteinase, and granzyme A (Felderhoff-Mueser et al., 2005; Mühl and Pfeilschifter, 2004).

6.

Glucocorticoids, IL-18 and HPA axis

The localization of IL-18 in the adrenal and pituitary gland and its pattern of expression during stress and ACTH suggested that IL-18, like other cytokines (Turnbull and Rivier, 1999),

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could be a modulator of the HPA axis and serve as a regulator of its functions. At present only two studies have provided data relevant with this respect. One demonstrated that IL-18 null mice showed reduced basal and stress-induced levels of corticosterone (Seino et al., 2006) indicating that IL-18 may actually contribute to corticosteroid synthesis. Another showed that, unlike IL-1β, IL-18 does not appear to stimulate CRH release but rather to inhibit it (Tsagarakis et al., 1989; Tringali et al., 2005). Thus, the role of IL-18 in the modulation of the HPA axis remains largely to be investigated. An equally interesting and relevance question is whether GC can affect the production of IL-18 in the adrenal gland or

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immune cells/tissues. This subject is particularly important to understand the possible role of IL-18 as a modulator of immune functions during stress. In fact, IL-18 and GC are both synthesized in the adrenal cortex by ACTH but have opposite biological activity on immunomodulation. While GC exert their anti-inflammatory action partly by reducing NF-κB mediated transcription (Van der Burg and Van der Saag, 1996; Yamamoto and Gaynor, 2001), IL-18 is a pro-inflammatory cytokine and stimulates NF-kB dependent transcription (Matsumoto et al., 1997). In rats, six days of chronic treatment with slow release corticosterone pellets did not affect levels of rat adrenal IL-18 mRNA and did not inhibit its ACTH-stimulated upregulation

Fig. 2 – Schematic representation of the tissue specific usage of differential promoter of the rat IL-18 gene and of the IL-18 system. Rat IL-18 gene is organized of at least 7 exons; the starting codon is found in exon 3 while exons 1 and 2 are not translated (additional nontranslated exons were identified by sequencing the IL-18 cDNA obtained from the pituitary gland — not shown). Gene transcription is believed to occur in a stimulus-dependent tissue specific manner: promoter 1 (P1) is utilized in the cells of the adrenal cortex to increase IL-18 transcription during stress while promoter 2 (P2) is utilized by cells of the immune system during infection. It is not known whether para-sympathetic down-regulation of IL-18 occurs at the transcriptional level and through which promoter. Both P1- and P2-dependent transcripts encode the same inactive peptide (Pro-IL-18) that is matured and secreted by caspase-1. Secreted IL-18 can bind the IL-18 binding protein (IL-18BP) that prevents its action, or the IL-18 receptor complex composed of the two subunits IL-18Rα (IL-1R5) and IL-18RAcP (IL-1R7) Upon binding, IL-18 can activate the IL-1 receptor-activating kinase (IRAK) or the mitogen activating protein kinase (MAPK) pathway leading to the activation of the nuclear factor-kappa beta (NF-κB) or STAT3 mediated transcription.

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(Conti et al., 2000), suggesting that GC do not modulate the production of IL-18 in the adrenal gland. However, the few studies carried out did not provide a clear understanding of the effect of GC on the production of IL-18. For instance, reduction of IL-18 level was observed in the serum of corticosteroid-responding patients with Graves' ophthalmopathy treated orally with the synthetic corticosteroid prednisone (Mysliwiec et al., 2003). In addition, in vitro steroid treatment had a partial, time and dose dependent suppression of LPS/IL-2 induced IL-18 production in human peripheral blood mononuclear cells PBMC (Kodama et al., 2002). By contrast, a separate in vitro study demonstrated that prednisone increased IL-18 expression and release in PBMC and U937 cells (Moller et al., 2002). Thus, GC may affect IL-18 production in the immune cell/tissue in the cell/ tissue type specific manner. Further studies are needed to address this subject.

7.

Parasympathetic down-regulation of IL-18

Although most of the work on the CNS dependent modulation of IL-18 has focused on its elevation during stress via the HPA axis, nicotine and acetylcholine have been shown to downregulate IL-18 levels. Nicotine inhibited the LPS primed synthesis of IL-18 in monocytes through alpha 7-nAChR (Takahashi et al., 2006a) and reduced the IL-18-initiated immune response by inhibiting the expression of several cytokines and co-stimulatory molecules including IL-12, IFN-γ, and TNF-α, a mechanism requiring PGE2 (Takahashi et al., 2006b). The down-regulation of IL-18 release that can be achieved through the vagus nerve is mediated by acetylcholine (Borovikova et al., 2000). Altogether these results indicate that the para-sympathetic nervous system can down-regulate IL-18. Interestingly, since para-sympathetic nervous system is activated by relaxation, it is possible that stress and relaxation may have opposite action on IL-18 levels and that specific mechanisms may have evolved to modulate not only neurogenic-dependent elevation but also reduction of IL-18 levels.

8. Biological roles of IL-18 and clinical relevance 8.1.

Peripheral action

IL-18 has been recognized to have primarily an immunostimulatory and pro-inflammatory action and has been implicated in several pathologies including cancer, atherosclerosis and autoimmunity. IL-18 was originally identified as an interferon-gamma (IFN-γ) inducing factor (IGIF) in Th1 lymphocytes and NK cells – an action that IL-18 can exerts to a certain extent alone but primarily in synergy with IL-12 – thus directing the immune system toward a cell-mediated immune response, (Hunter et al., 1997; Kohno et al., 1997; Okamura et al., 1995; Robinson et al., 1997). With this respect it is important to consider that despite elevating IL-18 levels, stress was not reported to elevate IFN-γ levels. Since stress was not reported to increase the levels of IL-12 either it is likely that the elevation of IL-18 during stress is not sufficient to stimulate the synthesis of IFN-γ in the absence of this second signal. In

addition, stress-induced IL-18 may be modulated by circulating levels of IL-18BP, a possibility that has never been investigated. In addition to the regulation of IFN-γ, IL-18 actions include the induction of the synthesis of tumor necrosis factor alpha (TNF-α), IL-1β, IL-8 and intracellular adhesion moleculed-1 (ICAM-1) (Dinarello et al., 1998). In addition, not surprisingly, IL-18 was found to have anti-microbial activity with its production elevated following challenge with bacteria, fungi, protozoa, and viruses and correlated with host resistance (Kawakami et al., 1997; Pirhonen, 2001; Reddy, 2004; Tschoeke et al., 2006). In support of a physiological role of IL-18 as an antimicrobial agent is the finding that human poxviruses, ectromelia, vaccinia and cowpox viruses encode secreted interleukin-18-binding-like proteins (Calderara et al., 2001; Cho et al., 2001; Smith et al., 2000; Xiang and Moss, 1999). Consistent with the immunostimulatory properties is the evidence that IL-18 may also play a role in the pathogenesis of the autoimmune diseases including diabetes, experimentally-induced encephalomyelitis and in human multiple sclerosis, rheumatoid arthritis and lupus erythematosus (Bossu et al., 2000; Esfandiari et al., 2001). IL-18 also possesses pro-apoptotic action. IL-18 increases Fas ligand expression of NK cells (Bossu et al., 2007) and stimulates Fas ligand-mediated cytotoxicity of Th1 cells (Dao et al., 1996), suggesting that IL-18 exerts pro-apoptotic action by enhancing the expression of Fas ligand (FasL) (Akita et al., 1997; Tsutsui et al., 1996). In addition, it has been reported that IL-18 stimulates perforin-mediated cytotoxicity (Dao et al., 1996, 1998). IL-18 has also been proposed to contribute to atherosclerosis (Hulthe et al., 2006; Mallat et al., 2001a,b; Whitman et al., 2002). The administration of IL-18 has been demonstrated to increase atherosclerosis by 2-fold both in the ascending aorta and the aortic arch (Whitman et al., 2002). The administration of exogenous IL-18 has been shown to promote the infiltration of T-lymphocytes in the atherosclerotic lesion (Whitman et al., 2002). These actions are believed to be mediated through IL-18-induced IFN-γ and by the direct effect of IL-18 on endothelial cells, smooth muscle cells and macrophages expressing the IL-18R complex (Gerdes et al., 2002). It was also demonstrated that IL-18 mediates expression of inflammatory genes in vascular smooth cells, an action enhanced by angiotensin II, and that the pro-atherogenic effects of IL-18 can occur via enhanced IFN-γ and CXCL16 independently of T-cells (Sahar et al., 2005; Tenger et al., 2005). Since a number of studies have demonstrated that psychological stress contribute to the development of atherosclerosis as well as ischemic heart diseases (Black, 2002; Bosma et al., 1997; Kop, 1997, 1999; Krantz et al., 1996; Lampert et al., 2000; Muller et al., 1994; Vale, 2005; Williams and Littman, 1996; Yan et al., 2003), it would be interesting to investigate the possibility that IL-18 is a possible mediator of atherosclerosis during stress. Finally, IL-18 has been investigated for its action on tumor progression. The results are apparently contradictory, reporting either a role of IL-18 in promoting or in reducing tumor progression. For instance, IL-18 correlates with the poor recovery in patients with multiple myeloma (Alexandrakis et al., 2004) or esophageal carcinoma (Tsuboi et al., 2004) and its serum level is elevated in patients with metastatic breast cancer compared to the non-metastatic condition of healthy

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subjects (Gunel et al., 2002). However, several studies demonstrated anti-tumor effects of IL-18 (Reviewed in Mühl and Pfeilschifter, 2004). The effect of IL-18 on the tumors may be complicated depending on tumor types. As reviewed and summarized by Dinarello (2006b), these apparent paradoxical actions may be due to anti-tumor action of IL-18 as an inducer of IFN-γ and a stimulator of NK activity opposed to its stimulation of tumor invasiveness for its role in inducing vascular adhesion molecules.

8.2.

Central action

The findings that IL-18 was expressed in microglia and astrocytes suggested that IL-18 may exert neuroinflammatory roles in the brain during infection, neurotrauma or neurodegenerative diseases (Conti et al., 1999; Culhane et al., 1998; Prinz and Hanisch, 1999; Wheeler et al., 2000, 2003a). A role for IL-18 in regulating microglial activation in the brain following infection came from studies demonstrating that IL-18 null mice have impaired clearance of neurovirulent influenza A virus from infected neurons in the brain (Mori et al., 2001) and impaired microglial transformation with reduced Iba1 expression, a calcium-binding protein that controls phagocytic functions (Mori et al., 2001). In the absence of infection IL-18 deficient mice also showed diminished stress-induced morphological microglial hypertrophy (Sugama et al., 2007). The report that in the hypoxic–ischemic brain IL-18 expression was localized to phagocytic microglia infiltrating necrotic lesion (Jander et al., 2002) indicated that IL-18 may have a role in stroke although this hypothesis remains controversial. One study found that the volume of infarction was significantly reduced in IL-18 deficient mice compared with wild type mice (Hedtjarn et al., 2002), while another reported that lack of IL-18 did not change the infarct volume in a middle cerebral artery occlusion model (Wheeler et al., 2003b). In an experimental model of Parkinson's disease that utilized injection of the dopaminergic specific neurotoxin MPTP the number of activated microglial cells in the substantia nigra of IL-18 deficient mice was reduced compared to wild type (Sugama et al., 2004). Finally, the levels of IL-18 transcript and protein were increased in the frontal lobe of Alzheimer's disease (AD) patients compared to healthy age-matched control. In these brains IL-18 was found in microglia, strocytes and in neurons to co-localize with amyloid-βplaques and with tau (Ojala et al., in press). An association between IL-18 gene polymorphisms and outcome of AD was also found (Bossu et al., 2007). These results suggest that IL-18 may regulate neuroinflammation through microglial activation and may contribute to neurodegenerative diseases. A different and more intriguing central role of IL-18 is its action as modulator of neuronal function. IL-18 has been reported to reduce long term potentiation and NMDA receptor-mediated post synaptic potentials (EPSP) in rat hippocampus (Curran and O'connor 2001; Kanno et al., 2004). Preliminary studies in our laboratory suggest that these actions are the result of a direct action of IL-18 on neurons and may contribute to the central action of IL-18 on suppression of appetite (Netea et al., 2006; Zorrilla et al., 2007) and induction of sleep (Kubota et al., 2001), both demonstrated in rodents. These actions can be considered as components of the sickness syndrome that occurs during infection and is mediated by pro-inflammatory cytokines (Dantzer, 2001). Yet, in contrast

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to other proinflammatory cytokines such as IL-1β, TNF and IL-6, IL-18 does not induce fever, probably the single most recognizable sign of infection (Gatti et al., 2002).

9. Association of IL-18 with psychiatric disorders Data obtained in humans or in animal models demonstrated an association between IL-18 levels and psychiatric disorders. In rodents, IL-18 transcript levels were elevated in the neocortex of depressed Long–Evans rats in a model of social defeat (Kroes et al., 2006). In humans, serum levels of IL-18 were also elevated in depression and panic disorders and other stress paradigms (Kokai et al., 2002; Merendino et al., 2002) as well as in schizophrenic individuals where they could be downregulated by treatment with the antipsychotic dopamine antagonist risperidone (Lu et al., 2004; Tanaka et al., 2000). Whether IL-18 may be involved in the pathogenesis of psychiatric disorders or its levels are elevated simply as a consequence of the disorders remains to be determined.

10.

Concluding remarks

The experimental evidence collected so far indicate that IL-18 production can be modulated by the central nervous system that can elevate its production during stress through the HPA axis and can possibly down-regulate it through the parasympathetic nervous system. This regulation appears to be tissue specific and to occur through differential splicing and promoter usage of IL-18 gene suggesting the evolution of mechanisms specific for the neurogenic modulation of IL-18. At present this remains probably the most interesting aspect of the central regulation of IL-18 since it indicates the existence of specific molecular mechanisms for its regulation. The possible biological function of stress-induced IL-18 remains largely unknown and its investigation and relevance must be addressed in specific experimental models also considering the role that IL-18BP and the IL-18R may play in such a scenario. On one hand, stress-induced IL-18 may simply be a modulator of the HPA axis functions. On the other, it is possible that IL-18 may be a mediator of the CNS dependent modulation of immune functions. As reviewed, IL-18 is pleiotropic and has extensively been shown to exert roles in several inflammationassociated conditions including infection, autoimmunity, cancer and atherosclerosis. Since psychological stress or emotions have been reported to influence the susceptibility or the progression of these conditions, it will be interesting to investigate their effects in the presence or absence of IL-18. Some such experiments are being carried out in our laboratories and may help to elucidate the possible role of IL-18 as neuro-immuno-modulator and its role in health and diseases.

Acknowledgments This study was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports,

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Science and Technology of Japan, the Harold L. Dorris Neurological Research Institute and NIH AG028040.

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