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  • LJI308 br Conclusion br Introduction Interleukin


    Introduction Interleukin (IL)-18 [1] is a member of the IL-1 cytokine family activating corner stones of inflammatory signaling, among others nuclear factor (NF)-κB and p38 mitogen-activated protein kinase. Striking similarities exist between IL-1β and IL-18 including processing by caspase-1, an atypical mode of release, and a frequently pathogenic role in autoimmunity [2] and autoinflammation [3]. Despite widely shared characteristics with IL-1β, IL-18 also shows distinctive properties. Above all, IL-18 is crucial for interferon (IFN)-γ production by natural killer (NK) [4] and T LJI308 where it interacts with IL-12 to back Th1-like functions [1,2]. Derived from innate immune cells, IL-18 is thus an essential bridge to adaptive immunity. IFNγ, in turn, neither directly upregulates IL-18 expression [5] nor is part of signaling pathways directly triggering IL-18 release [6]. Notably, IL-18 is constitutively expressed not only in monocytic [7] but also in epithelial cells [8,9] indicating a vital role at biological barriers. Finally, IL-18 promotes FasL-induced cytotoxicity which may particularly affect liver pathology [10]. A secreted IL-18 binding protein was identified with two splice variants (human IL-18BPa/c) serving as decoy receptors for mature (but not pro-) IL-18. IL-18BPa is by far the most prevalent human variant and is referred to herein as IL-18BP. Although to some degree constitutive in murine spleen and human peripheral blood mononuclear cells (PBMC) [[11], [12], [13]], IL-18BP, precisely human IL-18BPa, is strongly upregulated by IFNγ [[13], [14], [15]] thus enabling negative feedback regulation of the IL-18/IFNγ-axis [16]. In fact, administration of IL-18 to humans increases IFNγ as well as IL-18BP production [17] and IL-18BP is elevated in clinical inflammation, among others in inflammatory bowel diseases [18]. Interestingly, intestinal epithelial cells are a major source of IL-18BP during experimental colitis [19], an observation concurring with its induction by IFNγ in human colon carcinoma cells [14,15]. IL18BP promoter analysis in human HepG2 [13] and DLD1 [20] cells identified a γ-activated site (GAS) near the transcriptional start site (TSS) as crucial for gene induction by IFNγ. Notably, either a complex consisting of interferon regulatory factor-1 and CCAAT/enhancer-binding-protein-β [13] or signal transducer and activator of transcription (STAT)-1 [20] drive IL18BP transcription by binding to this site in cell type-specific manner. IL-18BP is also increased in epithelial cells by STAT1-activating IL-27 [21,22]. Although leukocytic IL-18BP expression is increased under the influence of IFNγ [20,23,24], its gene induction in human PBMC or monocytic cells is diminished when directly compared to that of epithelial cells [20]. Since IFNγ is, however, generally regarded a potent monocyte activator [25], we set out to investigate differential IL-18BP expression in human monocytic and epithelial (-like) cells. Herein, we propose that epigenic mechanisms based on CpG methylation determine IL18BP inducibility and by doing so support cell type-specific tasks in host defense.
    Materials and methods
    Discussion Janus-faced properties of IL-18 which may depend on its local concentration are studied best in murine experimental colitis. Here, beneficial functions of IL-18 were detected [36] that connect to increased tissue protection by IL-22 [37], likely via suppression of its opponent IL-22 binding protein [38]. Since invasive microbial growth drives colitis, IL-18 may also ameliorate disease by inducing anti-microbial peptides, among others angiogenins and resistin-like molecule-β [39]. If, however, favorable levels of IL-18 are exceeded, pathological properties of the cytokine break though. Besides generally promoting IFNγ- and tumor necrosis factor (TNF)-α-mediated intestinal inflammation [40], IL-18 can impair maturation of mucin-producing globlet cells thereby assisting colitis [41]. Those hazardous properties of this cytokine stress the necessity to efficiently control IL-18 biological activity by IFNγ-induced IL-18BP. Notably, this mode of IFNγ-driven negative feedback regulation with intestinal epithelial cells as significant source of IL-18BP was recently confirmed to operate in vivo during dextran sodium sulfate-induced murine colitis [19].