Drug-Induced Immunomodulation of Cytokines
Interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), and platelet-activating factor (PAF) play critical roles in the induction of inflammatory and immune responses (1-4). These cytokines act synergistically to induce fever, initiate acute-phase protein synthesis, up-regulate neutrophil and macrophage antimicrobial activity, decrease serum iron and zinc concentrations, and induce tissue catabolism. These events are clearly beneficial in mounting an effective inflammatory and immune response to invading microorganisms and in tumor surveillance. However, proinflammatory cytokines also have adverse effects on the body. Proinflammatory cytokines appear to be involved in the manifestations of both acute and chronic diseases (3-7). TNF and IL-1 are involved in the induction of shock associated with gram-negative sepsis, trauma, and burns (3,4,8-10). Symptoms associated with IL-1 and/or TNF release include hypotension, depressed myocardial function, vascular leakage, microvascular thrombosis, tissue neutrophilic infiltration and necrosis, and multiple organ failure. Chronic production of proinflammatory cytokines is an essential part of the cachexia associated with inflammatory and neoplastic disorders (11-13). The 204cachexia is characterized by increased oxidation of amino acids, muscle proteolysis, and accelerated synthesis of acute-phase proteins in the liver. TNF is primarily responsible for initiating the proteolysis; however, TNF and IL-1 act synergistically. TNF and IL-1 also induce hypertriglyceridemia; however, the effect appears to be mediated by increased hepatic lipogenesis and VLDL production rather than lipolysis.