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.