Crossref journal-article
Rockefeller University Press
The Journal of Experimental Medicine (291)
Abstract

Interleukin (IL)-12 may be secreted as a bioactive T helper type 1 (Th1) cell–inducing heterodimer, as a monomer, or as an antagonistic homodimer. We analyzed the IL-12 produced by mouse splenic dendritic cells (DCs), human thymic DCs, and cultured human monocyte-derived DCs. IL-12 production required both a microbial or T cell–derived stimulus and an appropriate cytokine milieu. The different IL-12 forms were differentially regulated by the cytokines present rather than the stimulus used. IL-4 alone or together with granulocyte/macrophage colony-stimulating factor or interferon γ effectively enhanced the production of the bioactive heterodimer and selectively reduced the antagonistic homodimer of IL-12. Therefore, IL-4, the major Th2-driving cytokine, provides a negative feedback causing DCs to produce the major Th1-inducing cytokine, bioactive IL-12.

Bibliography

Hochrein, H., O’Keeffe, M., Luft, T., Vandenabeele, S., Grumont, R. J., Maraskovsky, E., & Shortman, K. (2000). Interleukin (Il)-4 Is a Major Regulatory Cytokine Governing Bioactive IL-12 Production by Mouse and Human Dendritic Cells. The Journal of Experimental Medicine, 192(6), 823–834.

Authors 7
  1. Hubertus Hochrein (first)
  2. Meredith O'Keeffe (additional)
  3. Thomas Luft (additional)
  4. Stéphane Vandenabeele (additional)
  5. Raelene J. Grumont (additional)
  6. Eugene Maraskovsky (additional)
  7. Ken Shortman (additional)
References 52 Referenced 297
  1. 10.1084/jem.170.3.827 / J. Exp. Med. / Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes by Kobayashi (1989)
  2. 10.4049/jimmunol.146.9.3074 / J. Immunol / Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells by Wolf (1991)
  3. 10.1073/pnas.88.10.4143 / Proc. Natl. Acad. Sci. USA. / Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor by Gubler (1991)
  4. 10.1016/S0065-2776(08)60387-9 / Adv. Immunol. / Interleukin-12a cytokine at the interface of inflammation and immunity by Trinchieri (1998)
  5. 10.1146/annurev.immunol.16.1.495 / Annu. Rev. Immunol. / The interleukin-12/interleukin-12-receptor systemrole in normal and pathologic immune responses by Gately (1998)
  6. 10.1084/jem.176.5.1387 / J. Exp. Med. / Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells by D'Andrea (1992)
  7. 10.4049/jimmunol.158.9.4381 / J. Immunol. / In vivo production and function of IL-12 p40 homodimers by Heinzel (1997)
  8. 10.1002/eji.1830250133 / Eur. J. Immunol. / Mouse interleukin-12 (IL-12) p40 homodimera potent IL-12 antagonist by Gillessen (1995)
  9. 10.4049/jimmunol.154.1.116 / J. Immunol. / Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity by Ling (1995)
  10. 10.1002/eji.1830230923 / Eur. J. Immunol. / The interleukin-12 subunit p40 specifically inhibits effects of the interleukin-12 heterodimer by Mattner (1993)
  11. 10.1007/s001250050728 / Diabetologia / Suppression of cyclophosphamide induced diabetes development and pancreatic Th1 reactivity in NOD mice treated with the interleukin (IL)-12 antagonist IL-12(p40)2 by Rothe (1997)
  12. 10.1128/iai.65.11.4734-4737.1997 / Infect. Immun. / Treatment with homodimeric interleukin-12 (IL-12) p40 protects mice from IL-12-dependent shock but not from tumor necrosis factor alpha-dependent shock by Mattner (1997)
  13. 10.1111/j.1749-6632.1996.tb52650.x / Ann. NY Acad. Sci. / Interleukin-12 antagonist activity of mouse interleukin-12 p40 homodimer in vitro and in vivo by Gately (1996)
  14. 10.1073/pnas.93.17.9085 / Proc. Natl. Acad. Sci. USA. / Local production of the p40 subunit of interleukin 12 suppresses T-helper 1-mediated immune responses and prevents allogeneic myoblast rejection by Kato (1996)
  15. 10.1172/JCI2675 / J. Clin. Invest. / Local expression of immunoregulatory IL-12p40 gene prolonged syngeneic islet graft survival in diabetic NOD mice by Yasuda (1998)
  16. 10.4049/jimmunol.160.2.588 / J. Immunol. / Reduced T helper 1 responses in IL-12 p40 transgenic mice by Yoshimoto (1998)
  17. 10.1002/(SICI)1097-0215(19980729)77:3<460::AID-IJC24>3.0.CO;2-A / Int. J. Cancer. / Increased IL-12 P40 homodimer secretion by spleen cells during in vivo growth of the BW-19 T cell hybridoma accompanies suppression of natural immunity by Schmidt (1998)
  18. 10.4049/jimmunol.154.10.5071 / J. Immunol. / Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells by Macatonia (1995)
  19. 10.1002/eji.1830260323 / Eur. J. Immunol. / Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells by Heufler (1996)
  20. 10.1084/jem.184.2.741 / J. Exp. Med. / High level IL-12 production by murine dendritic cellsupregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10 by Koch (1996)
  21. 10.1084/jem.184.2.747 / J. Exp. Med. / Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacityT–T help via APC activation by Cella (1996)
  22. 10.4049/jimmunol.158.6.2919 / J. Immunol. / Bacterial lipopolysaccharide stimulates the production of cytokines and the expression of costimulatory molecules by human peripheral blood dendritic cellsevidence for a soluble CD14-dependent pathway by Verhasselt (1997)
  23. 10.1182/blood.V83.7.1847.1847 / Blood. / Differential regulation of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-1 beta production in human myeloid leukemia cell lines and peripheral blood mononuclear cells by Kubin (1994)
  24. 10.1182/blood.V86.2.646.bloodjournal862646 / Blood. / Regulation of interleukin-12 expression in human monocytesselective priming by interferon-gamma of lipopolysaccharide-inducible p35 and p40 genes by Hayes (1995)
  25. 10.4049/jimmunol.159.1.28 / J. Immunol. / IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells by Kalinski (1997)
  26. 10.1084/jem.181.2.537 / J. Exp. Med. / Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cellspriming for IL-12 and tumor necrosis factor alpha production by D'Andrea (1995)
  27. 10.4049/jimmunol.151.11.6370 / J. Immunol. / Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN- gamma or IL-10 by de Waal Malefyt (1993)
  28. 10.4049/jimmunol.159.11.5705 / J. Immunol. / Priming with IL-4 and IL-13 during HIV-1 infection restores in vitro IL-12 production by mononuclear cells of HIV-infected patients by Marshall (1997)
  29. 10.4049/jimmunol.156.3.1207 / J. Immunol. / Regulation of bioactive IL-12 production in lipopolysaccharide-stimulated human monocytes is determined by the expression of the p35 subunit by Snijders (1996)
  30. 10.1046/j.1365-2567.1999.00711.x / Immunology. / Interleukin-4 regulation of human monocyte and macrophage interleukin-10 and interleukin-12 production. Role of a functional interleukin-2 receptor gamma-chain by Bonder (1999)
  31. 10.4049/jimmunol.156.3.1196 / J. Immunol. / Regulation of murine macrophage IL-12 production. Activation of macrophages in vivo, restimulation in vitro, and modulation by other cytokines by Skeen (1996)
  32. 10.1002/jlb.61.1.80 / J. Leukoc. Biol. / Regulation of T cell-dependent and -independent IL-12 production by the three Th2-type cytokines IL-10, IL-6, and IL-4 by Takenaka (1997)
  33. 10.1038/386336a0 / Nature. / Bacterial DNA causes septic shock by Sparwasser (1997)
  34. 10.1084/jem.176.1.47 / J. Exp. Med. / The surface phenotype of dendritic cells purified from mouse thymus and spleeninvestigation of the CD8 expression by a subpopulation of dendritic cells by Vremec (1992)
  35. 10.4049/jimmunol.159.2.565 / J. Immunol. / Dendritic cell subtypes in mouse lymphoid organscross-correlation of surface markers, changes with incubation, and differences among thymus, spleen, and lymph nodes by Vremec (1997)
  36. 10.1002/eji.1830260606 / Eur. J. Immunol. / Structure and chromosomal location of the mouse interleukin-12 p35 and p40 subunit genes by Tone (1996)
  37. 10.1093/nar/12.18.6951 / Nucleic Acids Res. / Post-transcriptional regulation of glyceraldehyde 3-phosphate-dehydrogenase gene expression in rat tissues by Piechaczyk (1984)
  38. 10.1084/jem.184.5.1953 / J. Exp. Med. / Dramatic increase in the numbers of functionally mature dendritic cells in mice treated with Flt3 ligandmultiple dendritic cell subpopulations identified by Maraskovsky (1996)
  39. 10.4049/jimmunol.164.6.2978 / J. Immunol. / CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen by Vremec (2000)
  40. 10.1073/pnas.96.3.1036 / Proc. Natl. Acad. Sci. USA. / Distinct dendritic cell subsets differentially regulate the class of immune response in vivo by Pulendran (1999)
  41. 10.1084/jem.186.11.1819 / J. Exp. Med. / In vivo microbial stimulation induces rapid CD40 ligand–independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas by Sousa (1997)
  42. 10.1084/jem.189.3.587 / J. Exp. Med. / CD8α1 and CD8α− subclasses of dendritic cells direct the development of distinct T helper cells in vivo by Maldonado-Lopez (1999)
  43. 10.4049/jimmunol.164.1.64 / J. Immunol. / Synergistic effects of IL-4 and IL-18 on IL-12-dependent IFN-gamma production by dendritic cells by Fukao (2000)
  44. 10.4049/jimmunol.157.5.2209 / J. Immunol. / Recombinant IL-4 aggravates experimental autoimmune uveoretinitis in rats by Ramanathan (1996)
  45. 10.1084/jem.187.3.307 / J. Exp. Med. / Endogenous interleukin 4 is required for development of protective CD4+ T helper type 1 cell responses to Candida albicans by Mencacci (1998)
  46. 10.1084/jem.169.1.59 / J. Exp. Med. / Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets by Heinzel (1989)
  47. 10.1084/jem.188.8.1547 / J. Exp. Med. / Uptake of Leishmania major amastigotes results in activation and interleukin 12 release from murine skin–derived dendritic cellsimplications for the initiation of anti-Leishmania immunity by von Stebut (1998)
  48. 10.1002/eji.1830260722 / Eur. J. Immunol. / Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response by Mattner (1996)
  49. 10.1002/(SICI)1521-4141(199802)28:02<687::AID-IMMU687>3.0.CO;2-N / Eur. J. Immunol. / Dendritic cells, but not macrophages, produce IL-12 immediately following Leishmania donovani infection by Gorak (1998)
  50. 10.4049/jimmunol.162.2.974 / J. Immunol. / Anti-TGF-beta treatment promotes rapid healing of Leishmania major infection in mice by enhancing in vivo nitric oxide production by Li (1999)
  51. 10.4049/jimmunol.159.10.5024 / J. Immunol. / Leishmania major-infected C3H mice treated with anti-IL-12 mAb develop but do not maintain a Th2 response by Hondowicz (1997)
  52. 10.4049/jimmunol.160.8.3627 / J. Immunol. / CpG oligodeoxynucleotides trigger protective and curative Th1 responses in lethal murine leishmaniasis by Zimmermann (1998)
Dates
Type When
Created 23 years, 1 month ago (July 26, 2002, 12:48 p.m.)
Deposited 2 years, 1 month ago (July 25, 2023, 6:41 a.m.)
Indexed 4 months, 3 weeks ago (April 9, 2025, 2:02 a.m.)
Issued 24 years, 11 months ago (Sept. 11, 2000)
Published 24 years, 11 months ago (Sept. 11, 2000)
Published Online 24 years, 11 months ago (Sept. 11, 2000)
Published Print 24 years, 11 months ago (Sept. 18, 2000)
Funders 0

None

@article{Hochrein_2000, title={Interleukin (Il)-4 Is a Major Regulatory Cytokine Governing Bioactive IL-12 Production by Mouse and Human Dendritic Cells}, volume={192}, ISSN={1540-9538}, url={http://dx.doi.org/10.1084/jem.192.6.823}, DOI={10.1084/jem.192.6.823}, number={6}, journal={The Journal of Experimental Medicine}, publisher={Rockefeller University Press}, author={Hochrein, Hubertus and O’Keeffe, Meredith and Luft, Thomas and Vandenabeele, Stéphane and Grumont, Raelene J. and Maraskovsky, Eugene and Shortman, Ken}, year={2000}, month=sep, pages={823–834} }