Role of proinflammatory cytokine inhibition in rheumatoid arthritis

Cytokines play a major role in the pathologic processes of rheumatoid arthr itis (RA). In response to one or more triggers yet unknown, the production of various cytokines by infiltrating and resident cells escapes regulatory mechanisms and causes inflammation, pain, and tissue destruction. Current d ata indicate that tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) are the key mediators of inflammation and the destructive process. In addition, IL-1, either as membrane-bound IL-1 alpha or secreted IL-1 bet a, inhibits the tissue repair process. Inhibiting the production, release, and/or action of these proinflammatory and prodestructive cytokines may be of benefit in the sustained treatment of chronic destructive disease. Based on in vivo data, animal experimental models, and clinical trials, blo cking the biological activity of TNF-alpha by soluble receptors (TNF-sR) or antibodies to TNF-alpha as well as the development of molecules that speci fically bind to membrane receptors such as IL-1 receptor antagonist (IL-1Ra ), are very promising approaches. This article discusses the inflammatory a nd destructive processes and describes the basic concept for treating RA. b y inhibiting the offending cytokines, particularly IL-1 and TNF-or. Further more, a new approach that consists of interfering in the production:of both TNF-alpha and IL-1 on monocyte-macrophages during their contact with stimu lated T helper type 1 (Th1) lymphocytes will be discussed.