Interleukin-4 synergizes with Raf-1 to promote long-term proliferation and activation of c-jun N-terminal kinase.
This report shows that interleukin-4 (IL-4), which plays a key role in regulating immune responses, fails to support cellular growth. We investigated whether this failure of IL-4 to promote growth was because of its unique inability to activate the Ras/Raf/Erk pathway. Consistent with other reports, expression in Ba/F3, a factor-dependent hematopoietic cell line, of either activated Q61KN-Ras or a hormone-inducible activated Raf-1, resulted in suppression of apoptosis but not in long-term growth. However, in the presence of IL-4, Ba/F3 cells that expressed either Q61KN-Ras or activated Raf-1 grew continuously at a rate comparable with that stimulated by IL-3. Investigation of the biochemical events associated with the stimulation of long-term growth showed that, as expected, the presence of activated Raf-1 resulted 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 hematopoietic cells proliferation is correlated not only with "mitogen activated" ERK activity, but also with JNK activity.
Levings
M K
MK
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Bessette
D C
DC
Schrader
J W
JW
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D006410:Hematopoiesis / Q000187:drug effects* / Q000502:physiology; D015847:Interleukin-4 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D018631:ras Proteins / Q000502:physiology*
D015847:Interleukin-4; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins