PI3K-mediated negative feedback regulation of IL-12 production in DCs

Abstract

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 (PI3K) negatively regulates IL-12 synthesis by DCs. We found that numerous stimuli that induced IL-12 production concomitantly elicited PI3K activation in DCs, but both PI3K−/− and PI3K inhibitor–treated DCs showed increased IL-12 production. Accordingly, an enhanced T helper type 1 (TH1) response was observed upon Leishmania major infection in PI3K−/− 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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Figure 1: PI3K−/− splenic DCs.
Figure 2: Enhanced IL-12 production in the absence of PI3K activity.
Figure 3: Enhanced IL-12 mRNA expression in PI3K−/− and wortmannin-treated DCs.
Figure 4: Enhanced p38 activity in PI3K−/− and wortmannin-treated PI3K+/+ BMDCs in response to LPS.
Figure 5: Resistant phenotype and TH1 response to L. major infection in BALB/c-PI3K−/− mice.

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Acknowledgements

We thank A. Miyajima for recombinant mGM-CSF, H. Kayo for his help in experiments and M. Motouchi and K. Furuichi for animal care. We also thank L. K. Clayton for valuable discussions and critical reading of the manuscript. Supported by a Grant-in-Aid for Scientific Research (B) (14370116) and a Grant-in Aid for Creative Scientific Research (13GS0015) from the Japan Society for the Promotion of Science, a Grant-in-Aid for Scientific Research on Priority Areas (C) (13226112, 14021110), a National Grant-in-Aid for the Establishment of a High-Tech Research Center in a Private University, a grant for the Promotion of the Advancement of Education and Research in Graduate Schools, and a Scientific Frontier Research Grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Correspondence to Shigeo Koyasu.

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Fukao, T., Tanabe, M., Terauchi, Y. et al. PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat Immunol 3, 875–881 (2002). https://doi.org/10.1038/ni825

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