IL-17 is an inflammatory cytokine produced primarily by a unique lineage of CD4 T cells that plays critical roles in the pathogenesis of multiple autoimmune diseases. IL-17RA is a ubiquitously expressed receptor that is essential for IL-17 biologic activity. Despite widespread receptor expression, the activity of IL-17 is most classically defined by its ability to induce the expression of inflammatory cytokines, chemokines, and other mediators by stromal cells. The lack of IL-17 responsiveness in mouse stromal cells genetically deficient in IL-17RA is poorly complemented by human IL-17RA, suggesting the presence of an obligate ancillary component whose activity is species specific. This component is IL-17RC, a distinct member of the IL-17R family. Thus, the biologic activity of IL-17 is dependent on a complex composed of IL-17RA and IL-17RC, suggesting a new paradigm for understanding the interactions between the expanded family of IL-17 ligands and their receptors.

Objective. Interleukin-33 (IL-33; or, IL-1F11) was recently identified as the ligand of the IL-1 family receptor T1/ST2. The aim of this study was to examine IL-33 production in human and mouse joints and to investigate the role of IL-33 and T1/ST2 in experimental arthritis.Methods. IL-33 expression was examined in human synovial tissue, rheumatoid arthritis (RA) synovial fibroblasts, and arthritic mouse joints. Mice with collagen-induced arthritis (CIA) were treated with blocking anti-ST2 antibody or control antibody beginning at the onset of disease. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (LN) cell responses were examined ex vivo, and joint messenger RNA (mRNA) was used for expression profiling.Results. IL-33 was highly expressed in human RA synovium. In cultured synovial fibroblasts, IL-33 expression was strongly induced by IL-1␤ and/or tumor necrosis factor ␣. Furthermore, IL-33 mRNA was detected in the joints of mice with CIA and increased during the early phase of the disease. Administration of a blocking anti-ST2 antibody at the onset of disease attenuated the severity of CIA and reduced joint destruction. Anti-ST2 antibody treatment was associated with a marked decrease in interferon-␥ production as well as with a more limited reduction in IL-17 production by ex vivo-stimulated draining LN cells. Finally, RANKL mRNA levels in the joint were reduced by anti-ST2 treatment.Conclusion. IL-33 is produced locally in inflamed joints, and neutralization of IL-33 signaling has a therapeutic effect on the course of arthritis. These observations suggest that locally produced IL-33 may contribute to the pathogenesis of joint inflammation and destruction.Interleukin-33 (IL-33; or, IL-1F11) was recently identified as a ligand for the orphan IL-1 family receptor T1/ST2. IL-33 is produced as a 30-kd propeptide and, like IL-1␤ and IL-18, is cleaved by caspase 1 to generate mature 18-kd IL-33, at least in vitro (1). Mature IL-33 has been reported to mediate its biologic effects via T1/ST2 binding by activating NF-B and MAP kinases (1). T1/ST2-dependent IL-33 responses resemble classic IL-1-like signaling, and several recent studies identified the IL-1 receptor accessory protein as the coreceptor involved in IL-33 signaling (2-4).A number of studies have established T1/ST2 (also referred to as ST2L) as a selective marker of both murine and human Th2 lymphocytes (for review, see ref.5). In addition, T1/ST2 is highly expressed on mast cells (6). Several recent reports describe a stimulatory effect of IL-33 on cytokine and chemokine secretion in mast cells (3,(7)(8)(9)(10), suggesting that, in addition to promoting Th2 responses, IL-33 exhibits proinflammatory potential by inducing the production of a number of inflammatory mediators in mast cells. T1/ST2 also exists as a soluble isoform (sST2) obtained by differential messenger RNA (mRNA) processing. Soluble ST2 is identical with the extracellular region of the long T1/ST2 isoform except

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IL-33 signals through ST2, which is expressed either as a full-length signaling receptor or a truncated soluble receptor that can suppress IL-33 activity. Previous data suggest that soluble ST2 mRNA in fibroblasts is coupled to a serum-inducible proximal promoter, while full-length ST2 expression in immune cells is directed from a distal promoter. In order to better understand the function of the alternative promoters and how they ultimately affect the regulation of IL-33, we generated a mouse in which the ST2 proximal promoter is deleted. Promoter deletion had no impact on ST2 expression in mast cells or their ability to respond to IL-33. In contrast, it resulted in a complete loss of both soluble and full-length ST2 mRNA in fibroblasts, which corresponded with both an inability to secrete soluble ST2 and a defect in IL-33 responsiveness. Importantly, in spite of the fibroblast defect, soluble ST2 concentrations were not reduced in the serum of naïve or allergenexposed knockout mice. In summary, we found that ST2 promoter usage is largely celltype dependent but does not dictate splicing. Moreover, the proximal promoter is not a major driver of circulating soluble ST2 under the conditions tested.

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