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 proinflamma tory cytokines by monocytes and macrophages, The promotion of allergic resp onses by IL-4 has been shown to be absolutely dependent on the transcriptio n factor STAT6. We report here that the inhibitory effects of IL-4 on the p roduction 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 wi th LPS alone, However, IL-4 still induced significant inhibition of the pro duction of TNF-alpha and IL-12 from STAT6 null macrophages that were stimul ated with the more physiologically relevant combination of LPS and IFN-gamm a, 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.