Glycogen synthase kinase-3 promotes the synergistic action of interferon-gamma on lipopolysaccharide-induced IL-6 production in RAW264.7 cells.
Macrophages are the major effector cells of the innate immune system. Their function requires the integration of signals from pathogens, such as those induced by lipopolysaccharide (LPS), and from the host, such as those induced by interferon-gamma (IFN-gamma). The priming by IFN-gamma of Toll-like receptor-induced macrophage activation has long been recognized, but the mechanisms underlying this priming action remain unclear. We report in this study that the priming of macrophage-derived RAW264.7 cells by IFN-gamma is highly dependent on glycogen synthase kinase-3 (GSK3). Cooperative interactions of GSK3 and signal transducer and activator of transcription-3 (STAT3) were revealed by the findings that GSK3 inhibitors, or knockdown of the GSK3 beta isoform, strongly reduced the activation of STAT3, but not STAT1, induced by IFN-gamma without affecting upstream signaling events, and GSK3 was associated with STAT3. Direct inhibition of STAT3 activation abolished the synergistic action of IL-6 production by IFN-gamma administered with LPS. Similarly, inhibition of GSK3 abolished the synergistic stimulation of IFN-gamma on IL-6 production, and GSK3 was recruited to the IFN-gamma receptor by co-treatment with IFN-gamma and LPS. These results demonstrate the dependency of macrophage priming by IFN-gamma on STAT3 and GSK3, providing novel targets for intervention.
Beurel
Eléonore
E
Department of Psychiatry and Behavioral Neurobiology, 1720 Seventh Avenue South, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
Jope
Richard S
RS
D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007371:Interferon-gamma / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000096743:Interferon gamma Receptor
D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007371:Interferon-gamma; D015850:Interleukin-6; D008070:Lipopolysaccharides; D019000:Phosphotyrosine; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C448021:glycogen synthase kinase 3 alpha