Signaling Pathways Regulated by Cytokines

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Interleukin-1 and TNF-a share common signal transduction pathways, and the key signaling molecules involved are targets for therapy [21,132]. The major pathways induced by catabolic cytokines involve signal transduction by the stress-activated protein kinases c-Jun N-terminal kinases (JNKs) and p38 kinases and the nuclear factor (NF)-kB/IkB pathway. In vitro studies in chondrocytes have shown that the p38 and JNK cascades mediate the induction of proteinases and proinflammatory genes by IL-1 and TNF-a. These pathways may also be activated by mechanical stress and cartilage matrix products via integrins and other receptor-mediated events [1,47,54,60]. Induction of IL-1 and TNFa gene expression by stress-induced pathways suggests a mechanism by which these cytokines may serve as secondary mediators [189].

Small-molecule inhibitors that specifically target cytokine-induced signaling molecules have been explored as potential therapies in models in vitro and in vivo. At least four isoforms of p38 mitogen-activated protein kinase (MAPK) exist [165], with different substrate specificities and differential effects on essential chondrocyte functions [17,174]. The development of specific p38 MAPK inhibitors that target adverse responses to inflammatory mediators has been the subject of intense investigation [48,138,235]. Several p38 MAPK inhibitors have antidestructive effects in animal models of inflammation [161,247]. The JNKs exist in humans as three isoforms, JNK-1, -2, and -3, which have been targeted for the development of small molecule inhibitors [28]. A potent JNK1/2 inhibitor, SP600125, blocks inflammation and joint damage in a model of rheumatoid arthritis [20]. Activated JNK is detected in OA, but not in normal cartilage [39], and JNK inhibition attenuates cytokine-induced chondrocyte responses [2,124,143]. However, the effects of JNK inhibitors in OA animal models have not yet been studied.

While small molecule inhibitors of the NF-kB pathway have efficacy in animal models of rheumatoid arthritis (RA) [183], less information directly relevant to OA is available. Nevertheless, many of the agents developed for treating OA, including diac-erhein, N-acetylglucosamine, and green tea polyophenols can, to some extent, inhibit IL-1-induced NF-kB activation [21]. Two IkB kinases, IKK-1 and IKK-2, phosphorylate IkB. Inhibitors have been developed that dissociate IkB from NF-kB, thereby permitting translocation of active NF-kB to the nucleus [141,166]. NF-kB mediates the expression of cytokines and chemokines induced by fibronectin fragments [177]. Inhibition of DNA-binding activity of NF-kB agents that deplete polyamine prevents the induction of IL-8 by TNF-a without promoting chondrocyte apoptosis [53]. A reduction in synovial inflammation often accompanies the reduction of joint damage by the inhibitors of any of the cytokine-induced pathways. When inflammation exists in the OA joint, it therefore becomes a primary therapeutic target [34].

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Arthritis Relief and Prevention

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