NEGATIVE FEEDBACK IN INFLAMMATION - THE R OLE OF ANTIINFLAMMATORY CYTOKINES

Transforming growth factor-beta (TGF beta), interferon-alpha (IFN alph a), interleukin-4 (IL4), IL10 and IL13 have the capacity for inhibitin g the production of inflammatory cytokines such as IL1, IL6, tumour ne crosis factor (TNF alpha), IL8 and the other chemokines. Consequently, these cytokines have been designated antiinflammatory cytokines. In a ddition, they can counteract the proinflammatory activities of IL1 and TNF, such as tissue factor induction involved in coagulation, or the expression of adhesion molecules on the endothelial cell surface. Furt hermore, IL4, IL10, IL13, TGF beta and IFN alpha can induce the produc tion of IL1 receptor antagonists (IL1ra) which specifically limit the activity of IL1. The main natural inhibitors of TNF are the soluble TN F receptors, the release of which is enhanced during inflammation. Cor ticoids also repress the production of proinflammatory cytokines but d o not affect or even enhance the production of antiinflammatory cytoki nes. IL6, as the main inducer of acute phase protein synthesis, can be considered an antiinflammatory cytokine. However, all proinflammatory producing cells are not similarly sensitive to the effects of antiinf lammatory cytokines. In addition, the nature and sequence of messages acting on the target cell may modify its reactivity to the negative si gnals delivered by the antiinflammatory cytokines. Finally, wide indiv idual heterogeneity amplifies the diversity of the inflammatory respon ses. Thus, the world of cytokines is a complex one, and the nature of signals and of responding cells as well as the sequences of events are the unique characteristics of an inflammatory process induced by infe ctious and non-infectious stimuli.