Signaling pathways activated by interferons

Interferons are pleiotropic cytokines that exhibit negative regulatory effects on the growth of normal and malignant hematopoietic cells in vitro and in vivo. There are two different classes of interferons, Type I (alpha, beta, and omega) and Type II (gamma) interferons. Although the precise mechanisms by which these cytokines exhibit their potent effects on hematopoiesis remain unknown, there has been considerable progress in our understanding of the cellular changes that occur upon engagement of interferon receptors. It is now well established that Type I interferons activate multiple signaling pathways in hematopoietic cells, a finding consistent with their pleiotropic biological effects. One major pathway in Type I IFN signaling involves activation of Stat- proteins and formation of complexes that translocate to the nucleus and bind to specific elements to regulate gene transcription. The activation of this pathway (Jak-Stat pathway) is apparently regulated by members of the Jak-family of kinases, which are constitutively associated with the Type I IFN receptor. In addition to the Jak-Stat pathway, multiple other Jak-kinase-dependent signaling cascades are activated, including the IRS-PI 3'-kinase pathway, a pathway involving the vav proto-oncogene product, and a pathway involving adaptor proteins of the Crk-family (CrkL and CrkII). The only Type II interferon, IFNgamma, also activates multiple Jak-kinase-dependent signaling cascades, including the Stat and Crk pathways. Recent evidence suggests that non-Stat pathways play a critical role in the generation of signals for both Type I and Type II interferons and may be the primary mediators of their growth inhibitory effects on hematopoietic cells.