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. 1996 May 1;97(9):2130–2138. doi: 10.1172/JCI118650

Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis.

K Uyemura 1, L L Demer 1, S C Castle 1, D Jullien 1, J A Berliner 1, M K Gately 1, R R Warrier 1, N Pham 1, A M Fogelman 1, R L Modlin 1
PMCID: PMC507288  PMID: 8621803

Abstract

T cell cytokines are known to play a major role in determining protection and pathology in infectious disease. It has recently become clear that IL-12 is a key inducer of the type 1 T cell cytokine pattern characterized by production of IFN-gamma. Conversely, IL-10 down-regulates IL-12 production and type 1 cytokine responses. We have investigated whether IL-12 and IL-10 might be involved in a chronic inflammatory reaction, atherosclerosis. In atherosclerotic plaques, we found strong expression of IFN-gamma but not IL-4 mRNAs as compared to normal arteries. IL-12 p40 mRNA and IL-12 p70 protein were also found to be abundant in atherosclerotic plaques. IL-12 was induced in monocytes in vitro in response to highly oxidized LDL but not minimally modified LDL. The cross-regulatory role of IL-10 was indicated by the expression of IL-10 in some atherosclerotic lesions, and the demonstration that exogenous rIL-10 inhibited LDL-induced IL-12 release. These data suggest that the balance between IL-12 and IL-10 production contributes to the level of immune-mediated tissue injury in atherosclerotsis.

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Selected References

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  1. Barnes P. F., Chatterjee D., Abrams J. S., Lu S., Wang E., Yamamura M., Brennan P. J., Modlin R. L. Cytokine production induced by Mycobacterium tuberculosis lipoarabinomannan. Relationship to chemical structure. J Immunol. 1992 Jul 15;149(2):541–547. [PubMed] [Google Scholar]
  2. Berliner J. A., Territo M. C., Sevanian A., Ramin S., Kim J. A., Bamshad B., Esterson M., Fogelman A. M. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest. 1990 Apr;85(4):1260–1266. doi: 10.1172/JCI114562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bogdan C., Vodovotz Y., Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991 Dec 1;174(6):1549–1555. doi: 10.1084/jem.174.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boom W. H., Liebster L., Abbas A. K., Titus R. G. Patterns of cytokine secretion in murine leishmaniasis: correlation with disease progression or resolution. Infect Immun. 1990 Dec;58(12):3863–3870. doi: 10.1128/iai.58.12.3863-3870.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clerici M., Lucey D. R., Berzofsky J. A., Pinto L. A., Wynn T. A., Blatt S. P., Dolan M. J., Hendrix C. W., Wolf S. F., Shearer G. M. Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science. 1993 Dec 10;262(5140):1721–1724. doi: 10.1126/science.7903123. [DOI] [PubMed] [Google Scholar]
  6. Cushing S. D., Berliner J. A., Valente A. J., Territo M. C., Navab M., Parhami F., Gerrity R., Schwartz C. J., Fogelman A. M. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5134–5138. doi: 10.1073/pnas.87.13.5134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. D'Andrea A., Aste-Amezaga M., Valiante N. M., Ma X., Kubin M., Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993 Sep 1;178(3):1041–1048. doi: 10.1084/jem.178.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. D'Andrea A., Rengaraju M., Valiante N. M., Chehimi J., Kubin M., Aste M., Chan S. H., Kobayashi M., Young D., Nickbarg E. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992 Nov 1;176(5):1387–1398. doi: 10.1084/jem.176.5.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Emeson E. E., Robertson A. L., Jr T lymphocytes in aortic and coronary intimas. Their potential role in atherogenesis. Am J Pathol. 1988 Feb;130(2):369–376. [PMC free article] [PubMed] [Google Scholar]
  10. Frostegård J., Nilsson J., Haegerstrand A., Hamsten A., Wigzell H., Gidlund M. Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937. Proc Natl Acad Sci U S A. 1990 Feb;87(3):904–908. doi: 10.1073/pnas.87.3.904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gately M. K., Desai B. B., Wolitzky A. G., Quinn P. M., Dwyer C. M., Podlaski F. J., Familletti P. C., Sinigaglia F., Chizonnite R., Gubler U. Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol. 1991 Aug 1;147(3):874–882. [PubMed] [Google Scholar]
  12. Germann T., Gately M. K., Schoenhaut D. S., Lohoff M., Mattner F., Fischer S., Jin S. C., Schmitt E., Rüde E. Interleukin-12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells. Eur J Immunol. 1993 Aug;23(8):1762–1770. doi: 10.1002/eji.1830230805. [DOI] [PubMed] [Google Scholar]
  13. Hansson G. K., Holm J., Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol. 1989 Jul;135(1):169–175. [PMC free article] [PubMed] [Google Scholar]
  14. Heinzel F. P., Sadick M. D., Holaday B. J., Coffman R. L., Locksley R. M. 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. J Exp Med. 1989 Jan 1;169(1):59–72. doi: 10.1084/jem.169.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Henney A. M., Wakeley P. R., Davies M. J., Foster K., Hembry R., Murphy G., Humphries S. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8154–8158. doi: 10.1073/pnas.88.18.8154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hoff H. F., Whitaker T. E., O'Neil J. Oxidation of low density lipoprotein leads to particle aggregation and altered macrophage recognition. J Biol Chem. 1992 Jan 5;267(1):602–609. [PubMed] [Google Scholar]
  17. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  18. Jougasaki M., Kugiyama K., Saito Y., Nakao K., Imura H., Yasue H. Suppression of endothelin-1 secretion by lysophosphatidylcholine in oxidized low density lipoprotein in cultured vascular endothelial cells. Circ Res. 1992 Sep;71(3):614–619. doi: 10.1161/01.res.71.3.614. [DOI] [PubMed] [Google Scholar]
  19. Kishikawa H., Shimokama T., Watanabe T. Localization of T lymphocytes and macrophages expressing IL-1, IL-2 receptor, IL-6 and TNF in human aortic intima. Role of cell-mediated immunity in human atherogenesis. Virchows Arch A Pathol Anat Histopathol. 1993;423(6):433–442. doi: 10.1007/BF01606532. [DOI] [PubMed] [Google Scholar]
  20. Kleindienst R., Xu Q., Willeit J., Waldenberger F. R., Weimann S., Wick G. Immunology of atherosclerosis. Demonstration of heat shock protein 60 expression and T lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions. Am J Pathol. 1993 Jun;142(6):1927–1937. [PMC free article] [PubMed] [Google Scholar]
  21. Kosugi K., Morel D. W., DiCorleto P. E., Chisolm G. M. Toxicity of oxidized low-density lipoprotein to cultured fibroblasts is selective for S phase of the cell cycle. J Cell Physiol. 1987 Mar;130(3):311–320. doi: 10.1002/jcp.1041300302. [DOI] [PubMed] [Google Scholar]
  22. Ku G., Thomas C. E., Akeson A. L., Jackson R. L. Induction of interleukin 1 beta expression from human peripheral blood monocyte-derived macrophages by 9-hydroxyoctadecadienoic acid. J Biol Chem. 1992 Jul 15;267(20):14183–14188. [PubMed] [Google Scholar]
  23. Libby P., Hansson G. K. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest. 1991 Jan;64(1):5–15. [PubMed] [Google Scholar]
  24. Liew F. Y., Millott S., Li Y., Lelchuk R., Chan W. L., Ziltener H. Macrophage activation by interferon-gamma from host-protective T cells is inhibited by interleukin (IL)3 and IL4 produced by disease-promoting T cells in leishmaniasis. Eur J Immunol. 1989 Jul;19(7):1227–1232. doi: 10.1002/eji.1830190712. [DOI] [PubMed] [Google Scholar]
  25. McMurray H. F., Parthasarathy S., Steinberg D. Oxidatively modified low density lipoprotein is a chemoattractant for human T lymphocytes. J Clin Invest. 1993 Aug;92(2):1004–1008. doi: 10.1172/JCI116605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  27. Munro J. M., van der Walt J. D., Munro C. S., Chalmers J. A., Cox E. L. An immunohistochemical analysis of human aortic fatty streaks. Hum Pathol. 1987 Apr;18(4):375–380. doi: 10.1016/s0046-8177(87)80168-5. [DOI] [PubMed] [Google Scholar]
  28. Pearce E. J., Caspar P., Grzych J. M., Lewis F. A., Sher A. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med. 1991 Jan 1;173(1):159–166. doi: 10.1084/jem.173.1.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pond L., Wassom D. L., Hayes C. E. Evidence for differential induction of helper T cell subsets during Trichinella spiralis infection. J Immunol. 1989 Dec 15;143(12):4232–4237. [PubMed] [Google Scholar]
  30. Rajavashisth T. B., Andalibi A., Territo M. C., Berliner J. A., Navab M., Fogelman A. M., Lusis A. J. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature. 1990 Mar 15;344(6263):254–257. doi: 10.1038/344254a0. [DOI] [PubMed] [Google Scholar]
  31. Ramshaw A. L., Parums D. V. Immunohistochemical characterization of inflammatory cells associated with advanced atherosclerosis. Histopathology. 1990 Dec;17(6):543–552. doi: 10.1111/j.1365-2559.1990.tb00794.x. [DOI] [PubMed] [Google Scholar]
  32. Roach T. I., Barton C. H., Chatterjee D., Blackwell J. M. Macrophage activation: lipoarabinomannan from avirulent and virulent strains of Mycobacterium tuberculosis differentially induces the early genes c-fos, KC, JE, and tumor necrosis factor-alpha. J Immunol. 1993 Mar 1;150(5):1886–1896. [PubMed] [Google Scholar]
  33. Sadick M. D., Heinzel F. P., Holaday B. J., Pu R. T., Dawkins R. S., Locksley R. M. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med. 1990 Jan 1;171(1):115–127. doi: 10.1084/jem.171.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Salgame P., Abrams J. S., Clayberger C., Goldstein H., Convit J., Modlin R. L., Bloom B. R. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science. 1991 Oct 11;254(5029):279–282. doi: 10.1126/science.254.5029.279. [DOI] [PubMed] [Google Scholar]
  35. Schuh J., Fairclough G. F., Jr, Haschemeyer R. H. Oxygen-mediated heterogeneity of apo-low-density lipoprotein. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3173–3177. doi: 10.1073/pnas.75.7.3173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schwartz D., Andalibi A., Chaverri-Almada L., Berliner J. A., Kirchgessner T., Fang Z. T., Tekamp-Olson P., Lusis A. J., Gallegos C., Fogelman A. M. Role of the GRO family of chemokines in monocyte adhesion to MM-LDL-stimulated endothelium. J Clin Invest. 1994 Nov;94(5):1968–1973. doi: 10.1172/JCI117548. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Scott P., Natovitz P., Coffman R. L., Pearce E., Sher A. Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. J Exp Med. 1988 Nov 1;168(5):1675–1684. doi: 10.1084/jem.168.5.1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Seder R. A., Gazzinelli R., Sher A., Paul W. E. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10188–10192. doi: 10.1073/pnas.90.21.10188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sieling P. A., Abrams J. S., Yamamura M., Salgame P., Bloom B. R., Rea T. H., Modlin R. L. Immunosuppressive roles for IL-10 and IL-4 in human infection. In vitro modulation of T cell responses in leprosy. J Immunol. 1993 Jun 15;150(12):5501–5510. [PubMed] [Google Scholar]
  40. Sieling P. A., Wang X. H., Gately M. K., Oliveros J. L., McHugh T., Barnes P. F., Wolf S. F., Golkar L., Yamamura M., Yogi Y. IL-12 regulates T helper type 1 cytokine responses in human infectious disease. J Immunol. 1994 Oct 15;153(8):3639–3647. [PubMed] [Google Scholar]
  41. Stemme S., Faber B., Holm J., Wiklund O., Witztum J. L., Hansson G. K. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3893–3897. doi: 10.1073/pnas.92.9.3893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Stemme S., Holm J., Hansson G. K. T lymphocytes in human atherosclerotic plaques are memory cells expressing CD45RO and the integrin VLA-1. Arterioscler Thromb. 1992 Feb;12(2):206–211. doi: 10.1161/01.atv.12.2.206. [DOI] [PubMed] [Google Scholar]
  43. Terkeltaub R., Banka C. L., Solan J., Santoro D., Brand K., Curtiss L. K. Oxidized LDL induces monocytic cell expression of interleukin-8, a chemokine with T-lymphocyte chemotactic activity. Arterioscler Thromb. 1994 Jan;14(1):47–53. doi: 10.1161/01.atv.14.1.47. [DOI] [PubMed] [Google Scholar]
  44. Tripp C. S., Wolf S. F., Unanue E. R. Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3725–3729. doi: 10.1073/pnas.90.8.3725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Witztum J. L., Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991 Dec;88(6):1785–1792. doi: 10.1172/JCI115499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Witztum J. L. The oxidation hypothesis of atherosclerosis. Lancet. 1994 Sep 17;344(8925):793–795. doi: 10.1016/s0140-6736(94)92346-9. [DOI] [PubMed] [Google Scholar]
  47. Xu Q., Kleindienst R., Waitz W., Dietrich H., Wick G. Increased expression of heat shock protein 65 coincides with a population of infiltrating T lymphocytes in atherosclerotic lesions of rabbits specifically responding to heat shock protein 65. J Clin Invest. 1993 Jun;91(6):2693–2702. doi: 10.1172/JCI116508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yamamura M., Uyemura K., Deans R. J., Weinberg K., Rea T. H., Bloom B. R., Modlin R. L. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. doi: 10.1126/science.254.5029.277. [DOI] [PubMed] [Google Scholar]
  49. Yamamura M., Wang X. H., Ohmen J. D., Uyemura K., Rea T. H., Bloom B. R., Modlin R. L. Cytokine patterns of immunologically mediated tissue damage. J Immunol. 1992 Aug 15;149(4):1470–1475. [PubMed] [Google Scholar]
  50. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. de Waal Malefyt R., Haanen J., Spits H., Roncarolo M. G., te Velde A., Figdor C., Johnson K., Kastelein R., Yssel H., de Vries J. E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991 Oct 1;174(4):915–924. doi: 10.1084/jem.174.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. van der Wal A. C., Becker A. E., van der Loos C. M., Das P. K. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994 Jan;89(1):36–44. doi: 10.1161/01.cir.89.1.36. [DOI] [PubMed] [Google Scholar]

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