ACTIVATION OF P38 MAP KINASE PATHWAY BY ERYTHROPOIETIN AND INTERLEUKIN-3

Activation of p38 MAP kinase (p38) as well as JNK/SAPK has been descri bed as being induced by a variety of environmental stresses such as os motic shock, ultraviolet radiation, and heat shock, or the proinflamma tory cytokines tumor necrosis factor-alpha and interleukin-1 (IL-3). W e found that the hematopoietic cytokines erythropoietin (Epo) and IL-3 , which regulate growth and differentiation of erythroids and hematopo ietic progenitors, respectively, also activate a p38 cascade. Immunobl ot analyses and in vitro kinase assay clearly showed that Epo and IL-3 rapidly and transiently phosphorylated and activated p38 in Epo- or I L-3-dependent mouse hematopoietic progenitor cells. p38 can generally be activated by the upstream kinase MKK3 or MKK6, However, in vitro ki nase assays in the immunoprecipitates with anti-MKK6 antibody and anti -phosphorylated MKK3/MKK6 antibody showed that activation of neither M KK3 nor MKK6 was detected after Epo or IL-3 stimulation, while osmotic shock clearly induced activation of both MKK3/MKK6 and p38. Together with previous observations, these results suggest that both p38 and JN K cascades play an important role not only in stress and proinflammato ry cytokine responses but also in hematopoietic cytokine actions. (C) 1997 by The American Society of Hematology.