IL-4 inhibits the production of TNF-alpha and IL-12 by STAT6-dependent and -independent mechanisms.
IL-4 promotes allergic responses and inhibits the production of proinflammatory cytokines by monocytes and macrophages. The promotion of allergic responses by IL-4 has been shown to be absolutely dependent on the transcription factor STAT6. We report here that the inhibitory effects of IL-4 on the production of TNF-alpha or IL-12 by macrophages had both STAT6-dependent and -independent components, depending on the stimuli. IL-4 failed to inhibit the release of TNF-alpha or IL-12 from STAT6 null macrophages stimulated with LPS alone. However, IL-4 still induced significant inhibition of the production of TNF-alpha and IL-12 from STAT6 null macrophages that were stimulated with the more physiologically relevant combination of LPS and IFN-gamma. These data show that STAT6 is required for the IL-4-mediated inhibition of the production of TNF-alpha and IL-12 stimulated by LPS alone, but that IL-4 also activates distinct, STAT6 independent mechanism(s) that inhibit the IFN-gamma-mediated enhancement of IL-12 and TNF-alpha production.
Levings
M K
MK
The Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
Schrader
J W
JW
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D014443:Tyrosine / Q000378:metabolism
D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015847:Interleukin-4; D014443:Tyrosine; D007371:Interferon-gamma