Therapeutic effects of IL1 inhibitors

Many of the biological effects of IL-1 are similar to those observed after a severe infection (see Table 1). As a mediator produced in response to microbial invasion, IL-1 will induce fever, myalgia, somnolence, vasodilation and shock, cause bone resorption, induce muscle proteolysis, and induce synthesis of acute phase proteins such as C-reactive protein, serum amyloid A, and fibrinogen by hepatocytes. II.-1 causes a decrease in plasma zinc and iron, which in turn inhibits growth of virulent bacteria. IL-1 also induces chemokines that are responsible for neutrophil and macrophage emigration to sites of injury, all to arm the host against pathogens. Recent reports of the acquisition of soluble IL-1 type II receptors and inhibitors of ICE by certain viruses underscores the importance of IL-1 in host defense.

IL-1 has been implicated in vivo in the pathogenesis of a variety of acute and chronic inflammatory diseases such as septic shock, rheumatoid arthritis and atherosclerosis. Synovial fluids contain IL-1, which acts as a potent stimulator of cartilage resorption. Synovial tissue macrophages also produce high levels of IL-1 (3 followed by IL-lra. Endogenously produced IL-lra levels may be a normal response to limit the proinflammatory, pathogenic effects of IL-1.

A number of naturally occurring inhibitors of IL-1 are present in serum. PGE2 suppresses the synthesis and release of IL-1. CRH inhibits IL-l-induced anorexia, sleep and prostaglandin synthesis. Corticosteroids suppress expression of IL-1 mRNA. TGF(3, IL-4, IL-10 and IL-13 inhibit IL-1 production. (3-meI-anocyte-stimulating hormone inhibits the synthesis and activities of IL-1.

The role of the natural antagonist, IL-lra, in normal physiology remains to be understood. IL-lra can block IL-l-induced T cell proliferation, although 50% inhibition of IL-1 biological effects in vitro requires a 10- to 500-fold excess amount of IL-lra. IL-lra does not alter in vitro T cell proliferative responses to mitogens, antigens or alloantigens. IL-lra blocks LPS-induced IL-8 production in mononuclear cells. IL-lra also decreases IL-2 receptors and secretion of IL-la, IL-1 (3, IL-2 and TNF in these cells in vitro. Several studies have shown that inhibition of IL-lra by neutralizing antibodies results in considerable exacerbation of inflammatory diseases. Thus, IL-lra plays a role in downregulating in vivo inflammatory reactions. In animal models, IL-l-induced hypotension can be inhibited by pretreating the animals with large doses of IL-lra. However, the large amounts of IL-lra (10000-fold molar excess, 2.5 g day" ' estimated for human use) required to counteract IL-l-mediated effects reduces the clinical usefulness of IL-lra. Thus, IL-lra as yet has no significant therapeutic potential in human phase III clinical trials for sepsis. However, the demonstrated proinflammatory effect of suppressing IL-lra in vivo suggests that improved delivery systems may make IL-lra more effective.

Other approaches to block IL-l-mediated responses include the use of IL-l-specific antibodies, IL-1 receptor-specific antibodies, soluble IL-1 receptors and inhibitors of ICE.

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