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

Nature Immunology volume 3, pages 875881 (2002) | Download Citation

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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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References

  1. 1.

    & Innate immunity: impact on the adaptive immune response. Curr. Opin. Immunol. 9, 4–9 (1997).

  2. 2.

    Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu. Rev. Immunol. 13, 251–276 (1995).

  3. 3.

    & Dendritic cell regulation of TH1-TH2 development. Nature Immunol. 1, 199–205 (2000).

  4. 4.

    et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).

  5. 5.

    , & Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675–680 (2001).

  6. 6.

    , , & Cellular responses to interferon-γ. Annu. Rev. Immunol. 15, 749–795 (1997).

  7. 7.

    & Role of antigen presenting cells in innate immune system. Arch. Immunol. Ther. Exp. 49, 47–52 (2001).

  8. 8.

    et al. IFN-γ production by antigen-presenting cells: mechanisms emerge. Trends Immunol. 22, 556–560 (2001).

  9. 9.

    et al. Signalling and transcription in T helper development. Annu. Rev. Immunol. 18, 451–494 (2000).

  10. 10.

    et al. The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu. Rev. Immunol. 16, 495–521 (1998).

  11. 11.

    & Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu. Rev. Immunol. 13, 437–457 (1995).

  12. 12.

    & Cytokines that regulate autoimmune responses. Curr. Opin. Immunol. 11, 670–676 (1999).

  13. 13.

    et al. IL-12 antagonism enhances apoptotic death of T cells within hepatic allografts from Flt3 ligand-treated donors and promotes graft acceptance. J. Immunol. 166, 5619–5628 (2001).

  14. 14.

    et al. Cytokine regulation of host defense against parasitic gastrointestinal nematodes: Lessons from studies with rodent models. Annu. Rev. Immunol. 15, 505–533 (1997).

  15. 15.

    & Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387, 673–676 (1997).

  16. 16.

    et al. Functions of phosphoinositide 3-kinases: implications for development, immunity, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 17, 615–675 (2001).

  17. 17.

    et al. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85α subunit of phosphoinositide 3-kinase. Nature Genet. 21, 230–235 (1999).

  18. 18.

    et al. Xid-like immunodeficiency in mice with disruption of the p85α subunit of phosphoinositide 3-kinase. Science 283, 390–392 (1999).

  19. 19.

    et al. Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice. Nature Immunol. 3, 295–304 (2002).

  20. 20.

    , , , & Regulation of protective immunity against Leishmania major in mice. Curr. Opin. Immunol. 10, 459–464 (1998).

  21. 21.

    , & Phosphatidylinositol 3-kinase-dependent activation of protein kinase C-ζ in bacterial lipopolysaccharide-treated human monocytes. J. Biol. Chem. 272, 16445–16452 (1997).

  22. 22.

    et al. Toll-like receptor 2-mediated NF-κB activation requires a Rac1-dependent pathway. Nature Immunol. 1, 533–540 (2000).

  23. 23.

    , & A novel function of phosphorothioate oligodeoxynucleotides as chemoattractants for primary macrophages. J. Immunol. 167, 2847–2854 (2001).

  24. 24.

    , , & Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase Cγ2. J. Exp. Med. 179, 673–680 (1994).

  25. 25.

    et al. TRANCE, a TNF family member, activates Akt/PKB through a signalling complex involving TRAF6 and c-Src. Mol. Cell 4, 1041–1049 (1999).

  26. 26.

    et al. CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity 13, 453–462 (2000).

  27. 27.

    et al. Interleukin (IL)-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J. Exp. Med. 192, 823–833 (2000).

  28. 28.

    et al. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J. 17, 6230–6240 (1998).

  29. 29.

    et al. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 18, 1845–1857 (1999).

  30. 30.

    , , & Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nature Immunol. 1, 311–316 (2000).

  31. 31.

    , & Cellular survival: a play in three Akts. Genes. Dev. 13, 2905–2927 (1999).

  32. 32.

    et al. Paralysis of dendritic cell IL-12 production by microbial products prevents infection-induced immunopathology. Immunity 11, 637–647 (1999).

  33. 33.

    , , , & Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nature Immunol. 3, 76–82 (2002).

  34. 34.

    , , , & Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

  35. 35.

    , & Studies with IL-10−/− mice: an overview. J. Leukoc. Biol. 61, 389–396 (1997).

  36. 36.

    et al. B lymphocytes regulate dendritic cell (DC) function in vivo: increased interleukin 12 production by DCs from B cell-deficient mice results in T helper cell type 1 deviation. J. Exp. Med. 192, 475–482 (2000).

  37. 37.

    , , , & Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol. Cell. Biol. 21, 893–901 (2001).

  38. 38.

    et al. Akt down-regulation of p38 signalling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells. J. Biol. Chem. 276, 30359–30365 (2001).

  39. 39.

    , , & IL-12 selectively regulates STAT4 via phosphatidylinositol 3-kinase and Ras-independent signal transduction pathways. Eur. J. Immunol. 30, 1425–1434 (2000).

  40. 40.

    , , , & Primary role for Gi protein signalling in the regulation of interleukin 12 production and the induction of T helper cell type 1 responses. J. Exp. Med. 191, 1605–1610 (2000).

  41. 41.

    , & Selective suppression of IL-12 production by chemoattractants. J. Immunol. 164, 3009–3017 (2000).

  42. 42.

    & Phosphoinositide 3-kinase: a key biochemical signal for cell migration in response to chemokines. Immunol. Rev. 177, 217–235 (2000).

  43. 43.

    , , & Wortmannin-sensitive activation of p70s6k by endogenous and heterologously expressed Gi-coupled receptors. J. Biol. Chem. 271, 8537–8540 (1996).

  44. 44.

    et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).

  45. 45.

    & Expression of functional IL-2 receptors on mature splenic dendritic cells. Eur. J. Immunol. 30, 1453–1457 (2000).

  46. 46.

    et al. Inducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses. J. Immunol. 166, 4446–4455 (2001).

  47. 47.

    et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 176, 1693–1702 (1992).

  48. 48.

    et al. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science 263, 235–237 (1994).

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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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Author notes

    • Takayuki Ota

    Present address: Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Affiliations

  1. Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

    • Taro Fukao
    • , Takayuki Ota
    • , Satoshi Matsuda
    •  & Shigeo Koyasu
  2. Department of Tropical Medicine and Parasitology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

    • Masanobu Tanabe
    •  & Tsutomu Takeuchi
  3. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

    • Yasuo Terauchi
    • , Tomoichiro Asano
    •  & Takashi Kadowaki

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The authors declare no competing financial interests.

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Correspondence to Shigeo Koyasu.

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DOI

https://doi.org/10.1038/ni825

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