The use of cytokine inhibitors has been a major progress in the treatment AMPK inhibitors of chronic inflammation. However, not all patients respond and response will be often lost when treatment is stopped. These clinical aspects indicate that other cytokines might be involved and we focus here on the role of IL 17. In addition, the chronic nature of joint inflammation may contribute to reduced response and enhanced chronicity. We had previously observed that patients not responding well to TNF inhibition had higher blood expression of synoviolin, an E3 ubiquitin ligase previously shown to be implicated in synovial hyperplasia in human and mouse rheumatoid arthritis. Therefore we studied the capacity of IL 17 to regulate synoviolin in human RA synoviocytes and in chronic reactivated streptococcal cell wall induced arthritis.

Chronic reactivated SCW induced arthritis was examined in IL 17R deficient and wild type mice. Synoviolin chemical compound library expression was analysed by real time RT PCR, Western Blot or immunostaining in RA synoviocytes and tissue, and p53 assessed by Western Blot. Apoptosis was detected by annexin V/ propidium iodide staining, SS DNA apoptosis ELISA kit or TUNEL staining and proliferation by PCNA staining. IL 17 receptor A, IL 17 receptor C or synoviolin inhibition were achieved by small interfering RNA or neutralizing antibodies. IL 17 induced sustained synoviolin expression in RA synoviocytes. Sodium nitroprusside induced RA synoviocyte apoptosis was associated with reduced synoviolin expression and was rescued by IL 17 treatment with a corresponding increase in synoviolin expression.

IL 17RC or IL 17RA RNA interference increased SNP induced apoptosis, and decreased IL 17 induced synoviolin. IL 17 rescued RA synoviocytes from apoptosis induced by synoviolin knockdown. IL 17 and TNF had additive effects on synoviolin expression Plastid and protection against apoptosis induced by synoviolin knowndown. In IL 17R deficient mice, a decrease in arthritis severity was characterized by increased synovial apoptosis, reduced proliferation and a marked reduction in synoviolin expression. A distinct absence of synoviolin expressing germinal centres in IL 17R deficient mice contrasted with synoviolin positive B cells and Th17 cells in synovial germinal centre like structures. IL 17 induction of synoviolin may contribute in part to RA chronicity by prolonging the survival of RA synoviocytes and immune cells in germinal centre reactions.

These results extend the role of IL 17 to synovial hyperplasia. In osteoarthritis, despite major progress Lonafarnib solubility regarding the identification and roles of catabolic mediators, further knowledge about factors regulating their expression is needed. In this line of thought, one recently identified class of molecules, the microRNA, has been found to add another level of regulation to gene expression by down regulating its target genes. miRNAs are 20 23 nucleotides long single stranded non coding RNA molecules that act as transcriptional repressors by binding to the 3 untranslated region of the target messenger RNA.