Although interleukin 12 (IL-12) production by dendritic cells (DCs) confers protection against harmful invasions by regulating both innate and adaptive immunity, its dysregulation may have detrimental effects on the host. We show here that phosphoinositide 3-kinase (P13K) negatively regulates IL-12 synthesis by DCs. We found that numerous stimuli that induced IL-12 production concomitantly elicited P13K activation in DCs, but both P13K−/− and P13K inhibitor-treated DCs showed increased IL-12 production. Accordingly, an enhanced T helper type I (TH1) response was observed upon Leishmania major infection in P13K−/− mice. Our findings indicate that a negative feedback mechanism exists that regulates IL-12 production during DC activation and may help prevent the excessive TH1 polarization that causes undesirable immune responses.
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