Objective: The pathogenesis of rheumatoid arthritis (RA) reflects an ongoing imbalance between proinflammatory and antiinflammatory cytokines. Interleukin‐20 (IL‐20) has proinflammatory properties for keratinocytes. In this study, we sought to determine whether IL‐20 is involved in RA.Methods: We analyzed IL‐20 levels in synovial fluid from RA patients. IL‐20 and its receptors were detected in RA synovial fibroblasts (RASFs), using immunohistochemical staining. The effect of IL‐20 on endothelial cells, neutrophils, and RASFs was investigated using MTT and migration assays. The expression of IL‐20 and its receptors in healthy rats and in rats with collagen‐induced arthritis (CIA) was also analyzed. Soluble IL‐20 receptor type I (sIL‐20RI) or sIL‐20RII was administered to rats with CIA by intramuscular electroporation, and the severity of arthritis was monitored.Results: RA patients expressed significantly higher levels of synovial fluid IL‐20 than did the rheumatic disease controls. IL‐20 and its receptors were expressed in the synovial membranes and RASFs. IL‐20 induced RASFs to secrete monocyte chemoattractant protein 1, IL‐6, and IL‐8, and it promoted neutrophil chemotaxis, RASF migration, and endothelial cell proliferation. Both IL‐20 and IL‐20RI were up‐regulated in the rat CIA model. In vivo, electroporated sIL‐20RI plasmid DNA decreased the severity of arthritis in the rats with CIA.Conclusion: IL‐20 was up‐regulated in the synovial fluid of RA patients and acted as a chemokine that attracted the migration of neutrophils and RASFs in vitro. The rat CIA model demonstrated that IL‐20 was involved in the pathogenesis of arthritis, because sIL‐20RI significantly reduced arthritis in rats with CIA. Thus, IL‐20 may modulate the incidence and severity of arthritis and play important roles at local sites of inflammation.

IL-20 is a proinflammatory cytokine of the IL-10 family that is involved in psoriasis, rheumatoid arthritis, atherosclerosis, and stroke. However, little is known about the role of IL-20 in bone destruction. We explored the function of IL-20 in osteoclastogenesis and the therapeutic potential of anti–IL-20 monoclonal antibody 7E for treating osteoporosis. Higher serum IL-20 levels were detected in patients with osteopenia and osteoporosis and in ovariectomized (OVX) mice. IL-20 mediates osteoclastogenesis by up-regulating the receptor activator of NF-κB (RANK) expression in osteoclast precursor cells and RANK ligand (RANKL) in osteoblasts. 7E treatment completely inhibited osteoclast differentiation induced by macrophage colony-stimulating factor (M-CSF) and RANKL in vitro and protected mice from OVX-induced bone loss in vivo. Furthermore, IL-20R1–deficient mice had significantly higher bone mineral density (BMD) than did wild-type controls. IL-20R1 deficiency also abolished IL-20–induced osteoclastogenesis and increased BMD in OVX mice. We have identified a pivotal role of IL-20 in osteoclast differentiation, and we conclude that anti–IL-20 monoclonal antibody is a potential therapeutic for protecting against osteoporotic bone loss.

Interleukin (IL)-20 is a proinflammatory cytokine of the IL-10 family and involved in rheumatoid arthritis, atherosclerosis, stroke, and osteoporosis. However, the pathophysiological roles of IL-20 in liver injury have not been extensively studied. We explored the involvement of IL-20 in liver injury and the therapeutic potential of IL-20 antagonists for treating liver fibrosis. Compared with normal liver tissue from healthy individuals, the amount of IL-20 was much higher in hepatocytes and hepatic stellate cells in liver biopsies from patients with fibrosis, cirrhosis, and hepatocellular carcinoma. Carbon tetrachloride (CCl₄) treatment induced IL-20 that further up-regulated the expression of transforming growth factor (TGF)-β1 and p21^WAF1 and resulted in cell cycle arrest in the Clone-9 rat hepatocyte cell line. IL-20 activated quiescent rat hepatic stellate cells (HSCs) and up-regulated TGF-β1 expression. IL-20 also increased TGF-β1, tumor necrosis factor (TNF)-α, and type I collagen (Col-I) expression, and promoted the proliferation and migration of activated HSCs. Serum IL-20 was significantly elevated in mice with short-term and long-term CCl₄-induced liver injury. In mice with short-term liver injury, anti-IL-20 monoclonal antibody (7E) and anti-IL-20 receptor (IL-20R1) monoclonal antibody (51D) attenuated hepatocyte damage caused by CCl₄, TGF-β1, and chemokine production. In mice with long-term liver injury, 7E and 51D inhibited CCl₄-induced cell damage, TGF-β1 production, liver fibrosis, HSC activation, and extracellular matrix accumulation, which was caused by the reduced expression of tissue inhibitors of metalloproteinases as well as increased metalloproteinase expression and Col-I production. IL-20R1-deficient mice were protected from short-term and long-term liver injury. Conclusion: We identified a pivotal role of IL-20 in liver injury and showed that 7E and 51D may be therapeutic for liver fibrosis. (Hepatology 2014;60:1003–1014)

Objective: Interleukin‐20 (IL‐20) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). We investigated whether anti–IL‐20 antibody treatment would modulate the severity of the disease in a collagen‐induced arthritis (CIA) rat model.Methods: We generated a CIA model by immunizing rats with bovine type II collagen. Rats with CIA were treated subcutaneously with anti–IL‐20 antibody 7E, with the tumor necrosis factor (TNF) blocker etanercept, or with 7E in combination with etanercept. Arthritis severity was determined according to the hind paw thickness, arthritis severity score, degree of cartilage damage, bone mineral density, and cytokine production, which were evaluated using radiologic scans, microfocal computed tomography, and enzyme‐linked immunosorbent assay. To analyze gene regulation by IL‐20, rat synovial fibroblasts (SFs) were isolated and analyzed for the expression of RANKL, IL‐17, and TNFα. We also used real‐time quantitative polymerase chain reaction analysis and flow cytometry to determine IL‐20–regulated RANKL in mouse osteoblastic MC3T3‐E1 cells and Th17 cells.Results: In vivo, treatment with 7E alone or in combination with etanercept significantly reduced the severity of arthritis by decreasing the hind paw thickness and swelling, preventing cartilage damage and bone loss, and reducing the expression of IL‐20, IL‐1β, IL‐6, RANKL, and matrix metalloproteinases (MMPs) in synovial tissue. In vitro, IL‐20 induced TNFα expression in SFs from rats with CIA. IL‐20 markedly induced RANKL production in SFs, osteoblasts, and Th17 cells.Conclusion: Selectively blocking IL‐20 inhibited inflammation and bone loss in rats with CIA. Treatment with 7E combined with etanercept protected rats from CIA better than treatment with etanercept alone. Our findings provide evidence that IL‐20 is a novel target and that 7E may be a potential therapeutic agent for RA.