Data is representative of two experiments, with n = 8 in each group. were immunized with type II collagen in complete Freund’s adjuvant (CFA) to induce arthritis, and treated with neutralizing antibody to IFN- and/or IL-4. Systemic IL-17, IFN-, and IL-4 were measured in serum. At the peak of disease, cytokine production was measured by ELISA of supernatants from spleen, lymph node and paw cultures. Paws were also scored for histologic severity of arthritis. Results Joint inflammation was associated with a higher ratio of systemic IL-17/IFN-. Neutralization of IFN- Diazepam-Binding Inhibitor Fragment, human accelerated the course of CIA and was associated with increased IL-17 levels in the serum and joints. The IFN-/IL-4/IL-17 responses in the lymphoid organ were distinct from such responses in the joints. Neutralization of IL-4 led to increased arthritis only in the absence of IFN- and was associated with increased bone and cartilage damage without an increase in the levels of IL-17. Conclusions IL-4 and IFN- both play protective roles in CIA, but through different mechanisms. Our data Diazepam-Binding Inhibitor Fragment, human suggests that the absolute level of IL-17 is not the only determinant of joint inflammation. Instead, the balance of Th1, Th2 and Th17 cytokines control the immune events leading to joint inflammation. Introduction IL-17 has recently been implicated in the pathogenesis of multiple autoimmune diseases, including rheumatoid arthritis (RA) and the mouse model collagen-induced arthritis (CIA). Patients with RA Rabbit polyclonal to EPM2AIP1 have higher levels of IL-17 in their serum and synovial fluid than normal controls or patients with osteoarthritis (OA) [1-3]. IL-17-producing Th17 cells are present in the T cell-rich areas of RA synovium  and induce the expression of receptor activator of NF-kB ligand (RANKL), which aids bone resorption [2,5,6]. Furthermore, high levels of mRNA for IL-17 and TNF- in the RA synovium are predictive of joint damage progression, while high levels of interferon (IFN)- mRNA are predictive of protection from damage . These findings indicate that IL-17 is Diazepam-Binding Inhibitor Fragment, human a key pathogenic cytokine that is relevant to the downstream events associated with autoimmune joint inflammation. In addition, studies that have employed strategies to up-regulate, neutralize or delete IL-17 have shown, quite consistently, that Th17 cells have a pathogenic role in CIA [8-10]. RA and CIA are complex diseases with requirements for systemic and target organ specific T cell and B cell activation, and these processes are positively and negatively regulated by multiple cytokine networks. em In vitro /em studies show that Th17 development is down-regulated by IFN- and IL-4, cytokines derived from Th1 and Th2 cells, respectively [11,12]. The role of IFN- in animal models of arthritis is complex, with evidence for both protective and pathogenic functions. Previous studies have found that mice deficient in either IFN- or IFN- receptor develop more severe CIA than wild type counterparts [13-16]. Proteoglycan-induced arthritis, on the other hand, is dependent on IFN- and independent of IL-17 [17,18]. IFN- clearly has the ability to induce inflammation in some settings, but it can also inhibit Th17 differentiation and thereby reduce inflammation. The net effect of IFN- may depend on the phase of disease and the location – such as the joint versus the spleen or lymph node. By administering neutralizing antibodies at different time points, one study suggested that IFN- has pathogenic effects in the early phase of disease but protective effects in the later stages . Although this study did not measure IL-17, one plausible interpretation of these results is that IFN- possibly takes on a protective role after Th17 cells become overabundant and highly pathogenic. Similar to IFN-, evidence for the role of IL-4 in arthritis is complex. IL-4-based interventions can Diazepam-Binding Inhibitor Fragment, human prevent or alleviate joint inflammation and bone damage in multiple animal models of arthritis [20-22]. We have shown previously that systemic injection of dendritic cells genetically engineered to produce IL-4 (IL-4 DCs) attenuates CIA . Further mechanistic studies revealed that IL-4 secreted from IL-4 DCs is a potent suppressor of IL-17 production by T cells from the early phase of CIA . These results suggest that endogenous IL-4 could also play a protective role in arthritis by suppressing IL-17 in the early phase of disease. However, it leaves open.
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