Inhibition of cytokine signaling

The pathways by which cytokines exert their biological effects have been a major focus of research over the past several years. Much of this work has defined the mechanisms by which binding of cytokines to their specific receptors initiates downstream signaling. This work has defined several major signaling pathways initiated by this process. Although the effect of most cytokines is limited in both magnitude and duration, the mechanisms responsible for this limitation have not been well studied. Most limitation of cytokine activity occurs through regulated production of cytokines. In addition, the developmentally regulated expression of cytokine receptors is an important mechanism utilized by the immune system to limit the biological effects of cytokines. More recent attention has been centered on the intracellular mechanisms used to limit cytokine signaling. There are several proposed mechanisms by which cytokine signaling is regulated within the cell. Tyrosine phosphatases can regulate the phosphorylation of various components in the signaling pathway. For example, the recruitment of SHP-1 to cytokine receptors (e.g., erythropoietin) is believed to regulate the duration and/or magnitude of cytokine signaling (1-4). In addition, there is some evidence that the stability of STAT proteins is altered after their activation by the targeting of phosphorylated STATs to the proteosome (5). Finally, PIAS proteins may limit the ability of STATs to bind DNA (6).