Interleukin-4 synergizes with Raf-1 to promote long-term proliferation andactivation of c-jun N-terminal kinase

This report shows that interleukin-4 (IL-4), which plays a key role in regu lating immune responses, fails to support cellular growth. We investigated whether this failure of IL-4 to promote growth was because of its unique in ability to activate the Ras/Raf/Erk pathway. Consistent with other reports, expression in Ba/F3, a factor-dependent hematopoietic cell line, of either activated N-Q61K-Ras or a hormone-inducible activated Raf-1, resulted in s uppression of apoptosis but not in long-term growth. However, in the presen ce of IL-4, Ba/F3 cells that expressed either N-Q61K-Ras or activated Raf-1 grew continuously at a rate comparable with that stimulated by IL-3, Inves tigation of the biochemical events associated with the stimulation of long- term growth showed that, as expected, the presence of activated Raf-1 resul ted In an increased activity of extracellular signal regulated kinase (ERK) mitogen-activated protein kinase (MAPK) but not of c-jun N-terminal kinase /stress-activated protein kinase (JNK). However, surprisingly, if IL-4 was present, cells expressing active Raf-1 exhibited increases in JNK activity. These observations point to a novel mechanism for JNK activation involving synergy between Raf-1 and pathways activated by IL-4 and suggest that in h ematopoietic cells proliferation is correlated not only with "mitogen activ ated" ERK activity, but also with JNK activity. (C) 1999 by The American So ciety of Hematology.