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Summary:  Cytokine-driven inflammation and tissue destruction is a common theme of chronic inflammatory diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, chronic obstructive pulmonary disease, and atherosclerosis. Research over the last two decades demonstrated the importance of cytokines that are not only expressed chronically but also are capable of signaling at sites of chronic inflammation. Cytokines thus regulate major pathological processes that include inflammation, angiogenesis, tissue remodeling, and fibrosis. This research led to the identification of key cytokines involved in these processes, two of which, tumor necrosis factor-α and interleukin-1, have also been successfully targeted in the clinic. However, what triggers and maintains cytokine gene expression in chronic inflammation remains a mystery. In this article, we review current progress in the understanding of cytokine-driven inflammation and discuss current evidence implicating Toll-like receptors (TLRs), recently identified as the receptors recognizing self versus non-self molecular patterns, in the regulation of cytokine-driven inflammation. Whether targeting TLRs and their downstream signaling pathway will prove to be a successful approach for the treatment of these devastating diseases remains to be determined.