Cytokines and cachexia

Prolonged production of cytokines associated with cancer and chronic infections, and other long-term immune reactions is increasingly recognized as a main causal factor of the often severe signs and symptoms that accompany these diseases: weight loss, anorexia, and metabolic breakdown termed cachexia. The cytokine that initially was held responsible for causing these changes was tumor necrosis factor (TNF). However, from various studies it has become clear that the action of TNF can only be understood in the context of simultaneous presence of other cytokines, some of which have activities that are at the least equally important as TNF in bringing about cachexia. This review summarizes the experimental evidence for the involvement of cytokines in the pathogenesis of cachexia. Indirect evidence comes from the observation that cachexia can be induced in animals by repeated injections of cytokines or by inoculation of cytokine-producing cells. Thus, cachexia has been described in mice inoculated with tumor cells carrying and expressing genes for either TNF, interleukin-6 (IL-6), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and interferon-gamma (IFN-gamma). More direct evidence is provided by the observations that cachexia in experimental animal models can be mitigated by administration of specific antagonists of cytokines. These latter type of studies revealed that cachexia can rarely, if ever, be attributed to one single cytokine but rather to a set of cytokines that work in concert in cachexia. A pool of anticytokine antibodies or other cytokine inhibitors might, therefore, be considered as a potential intervention for the treatment of cachectic patients, but this approach may induce immunosuppression, and, therefore, danger exists that such treatment may benefit the infectious agent or tumor.