Interleukin (IL)-1 was first cloned in the 1980s, and rapidly emerged as a key player in the regulation of inflammatory processes. The term IL-1 refers to two cytokines, IL-1alpha and IL-1beta, which are encoded by two separate genes. The effects of IL-1 are tightly controlled by several naturally occurring inhibitors, such as IL-1 receptor antagonist (IL-1Ra), IL-1 receptor type II (IL-1RII), and other soluble receptors. Numerous IL-1 inhibitors have been developed and tested primarily in rheumatoid arthritis, with only modest effects. By contrast, the use of IL-1 antagonists has been uniformly associated with beneficial effects in patients with hereditary autoinflammatory conditions associated with excessive IL-1 signaling, such as cryopyrinopathies and IL-1Ra deficiency. Successful treatment with IL-1 blockers has also been reported in other hereditary autoinflammatory diseases, as well as in nonhereditary inflammatory diseases, such as Schnizler syndrome, systemic-onset juvenile idiopathic arthritis and adult Still disease. The role of microcrystals in the regulation of IL-1beta processing and release has provided the rationale for the use of IL-1 inhibitors in crystal-induced arthritis. Finally, preliminary results indicating that IL-1 targeting is efficacious in type 2 diabetes and smoldering myeloma have further broadened the spectrum of IL-1-driven diseases.

IL-36␣ (IL-1F6), IL-36␤ (IL-1F8

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

ObjectivesRheumatoid arthritis (RA) has been associated with a relative expansion of faecal Prevotellaceae. To determine the microbiome composition and prevalence of Prevotella spp. in a group of individuals at increased risk for RA, but prior to the development of the disease.MethodsIn an ongoing cohort study of first-degree relatives (FDRs) of patients with RA, we identified ‘FDR controls’, asymptomatic and without autoantibodies, and individuals in pre-clinical RA stages, who had either developed anticitrullinated peptide antibodies or rheumatoid factor positivity and/or symptoms and signs associated with possible RA. Stool sampling and culture-independent microbiota analyses were performed followed by descriptive statistics and statistical analyses of community structures.ResultsA total of 133 participants were included, of which 50 were categorised as ‘FDR controls’ and 83 in ‘pre-clinical RA stages’. The microbiota of individuals in ‘pre-clinical RA stages’ was significantly altered compared with FDR controls. We found a significant enrichment of the bacterial family Prevotellaceae, particularly Prevotella spp., in the ‘pre-clinical RA’ group (p=0.04).Conclusions Prevotella spp. enrichment in individuals in pre-clinical stages of RA, before the onset of RA, suggests a role of intestinal dysbiosis in the development of RA.