Clinical implications of dysregulated cytokine production

Cytokines are soluble proteins that are produced and secreted as part of the immune response to a variety of tissue insults including infection, cancer, and autoimmunity. Most cytokines are secreted by cells of the immune system, but some (for example, type I interferons) are released from "nonimmunological" cells such as fibroblasts and epithelial cells. Cytokines have pleiotropic effects, acting on many somatic cell types to modulate the host's immune response. For the most part, cytokines exert their antimicrobial actions locally---they are secreted by cells in the area of infection, and their effects are restricted to neighboring cells. While many of their local effects benefit the host, cytokines are soluble molecules that may act systemically and are often responsible for many of the symptoms of infection (e.g., headache, fever, myalgia). In high concentrations they can be toxic, or even lethal. Human clinical trials involving the systemic injection of purified cytokines such as interleukins 2 and 12 and tumor necrosis factor alpha provide compelling evidence for the toxicity of these molecules. Likewise, studies of septic shock syndrome demonstrate how overproduction/aberrant production of inflammatory cytokines can lead to rapid mortality. The host may attempt to counter high cytokine levels by releasing soluble cytokine receptors (sCR) or by synthesizing high-affinity anti-cytokine antibodies (acAb), and these natural responses have spawned great interest as potential therapeutic approaches for alleviating cytokine-mediated disease. However, recent studies indicate that these in vivo interactions are much more complex than previously realized; administration of sCR or acAb may either inhibit or (paradoxically) enhance cytokine activity. An alternative therapeutic approach is to intervene at the source of cytokine production. T cells initiate cytokine production only upon antigen contact and terminate synthesis almost immediately after this contact is broken. Thus T cells secrete cytokines specifically at sites of infection and do not continuously produce these potentially toxic molecules while migrating through uninfected tissues or the bloodstream. By learning more about the molecular mechanisms involved with on/off regulation of cytokine production we may be able to develop novel therapeutic drugs to protect against cytokine-mediated immunopathology. This review discusses the regulation of cytokine function by sCR and acAb and compares this to the regulatory mechanisms that are associated with antigen-specific cytokine release by T cells.