Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1

Interferon (IFN)-alpha has proven useful for treating several clinical cond itions, including chronic viral hepatitis and chronic myeloproliferative an d lymphoproliferative disorders. In addition to its well-known antiviral ef fects, the cytokine exerts antiproliferative effects on many cell types, he lping to explain its therapeutic usefulness in these latter conditions. How ever, this same property accounts for several undesirable effects, includin g thrombocytopenia, which can interfere with the successful clinical applic ation of IFN-alpha. Unfortunately, the mechanisms responsible for the myelo suppressive effects of the cytokine are incompletely understood. The effect s of IFN-alpha on megakaryocyte (MK) development were studied. Using severa l marrow cell purification techniques and quantitative culture methods, it was found that IFN-alpha directly inhibits thrombopoietin (TPO)induced MK g rowth. Previous studies indicated that Janus kinase (JAK) and its substrate s mediate the effects of TPO on cellular proliferation and survival. It was found that IFN-alpha directly suppresses TPO-induced phosphorylation of th e JAK2 substrates c-Mpl and STAT 5 in a TPO-dependent hematopoietic cell li ne and of Mpl and STAT3 in primary murine MK, Moreover, IFN-alpha induces S OCS-1 production in these cells, which has been shown to inhibit TPO-induce d cell growth. Because SOCS protein expression is induced by many cytokines and has been reported to extinguish signaling from several hematopoietic c ytokine receptors, these results identify a molecular mechanism responsible for cytokine receptor cross-talk (Blood, 2000;96:2093-2099) (C) 2000 by Th e American Society of Hematology.