Interferon-gamma has dual potentials in inhibiting or promoting cell proliferation.
Many cytokines have dual functions of promoting or inhibiting cell proliferation; however, the molecular mechanism of the dual functions of cytokines is not well understood. Under normal conditions, interleukin (IL)-3 is required for Ba/F3 cell proliferation, whereas interferon (IFN)-gamma inhibits Ba/F3 cell proliferation. It is known that Stat1 play a major role in inhibition of cell growth in response to IFN-gamma. We have examined the possibility of whether IFN-gamma can act as a growth-promoting cytokine if the Stat1 function is selectively blocked. We have established variant Ba/F3 cell lines in which Stat1 function is inhibited by a dominant-negative Stat1 mutant. Intriguingly, once Stat1 function is inhibited, IFN-gamma can replace IL-3 acting as an essential growth factor for cell proliferation. To understand the molecular mechanism of regulation of cell proliferation by the cytokines, the signaling pathways and gene induction by IL-3 and IFN-gamma are further studied. Although IL-3 activates mitogenic-activated protein kinase and Akt kinase, IFN-gamma does not. Interestingly, both IL-3 and IFN-gamma induce expression of the c-Myc gene that is not dependent on the Stat1 activity. Expression of a dominant-negative mutant Myc can block IFN-gamma-mediated Ba/F3 cell proliferation, suggesting that c-Myc gene induction is required for IFN-gamma-mediated cell proliferation. These findings suggest that IFN-gamma intrinsically and simultaneously induces specific and conflicting signaling pathways and transcriptional programs that contribute to the potential dual effects of IFN-gamma in promoting or inhibiting cell proliferation.
Asao
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Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Fu
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D019943:Amino Acid Substitution; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D004268:DNA-Binding Proteins; D007377:Interleukin-3; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D004247:DNA