Home LiteratureArticle Details
PMID: 7905017 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection.

The Journal of experimental medicine ·Vol. 179 ·No. 2 ·1994-02-01 ·Pages 447-56

Reiner SL, Zheng S, Wang ZE, Stowring L, Locksley RM

Abstract

Leishmania major are intramacrophage parasites whose eradication requires the induction of T helper 1 (Th1) effector cells capable of activating macrophages to a microbicidal state. Interleukin 12 (IL-12) has been recently identified as a macrophage-derived cytokine capable of mediating Th1 effector cell development, and of markedly enhancing interferon gamma (IFN-gamma) production by T cells and natural killer cells. Infection of macrophages in vitro by promastigotes of L. major caused no induction of IL-12 p40 transcripts, whereas stimulation using heat-killed Listeria or bacterial lipopolysaccharide induced readily detectable IL-12 mRNA. Using a competitor construct to quantitate a number of transcripts, a kinetic analysis of cytokine induction during the first few days of infection by L. major was performed. All strains of mice examined, including susceptible BALB/c and resistant C57BL/6, B10.D2, and C3H/HeN, had the appearance of a CD4+ population in the draining lymph nodes that contained transcripts for IL-2, IL-4, and IFN-gamma (and in some cases, IL-10) that peaked 4 d after infection. In resistant mice, the transcripts for IL-2, IL-4, and IL-10 were subsequently downregulated, whereas in susceptible BALB/c mice, these transcripts were only slightly decreased, and IL-4 continued to be reexpressed at high levels. IL-12 transcripts were first detected in vivo by 7 d after infection, consistent with induction by intracellular amastigotes. Challenge of macrophages in vitro confirmed that amastigotes, in contrast to promastigotes, induced IL-12 p40 mRNA. Reexamination of the cytokine mRNA at 4 d revealed expression of IL-13 in all strains analyzed, suggesting that IL-2 and IL-13 may mediate the IL-12-independent production of IFN-gamma during the first days after infection. Leishmania have evolved to avoid inducing IL-12 from host macrophages during transmission from the insect vector, and cause a striking induction of mRNAs for IL-2, IL-4, IL-10, and IL-13 in CD4+ T cells. Each of these activities may favor survival of the organism.

MeSH Terms
Animals Base Sequence CD4-Positive T-Lymphocytes/immunology Cell Line Cytokines/biosynthesis DNA Primers Interleukin-12 Interleukin-4/biosynthesis Interleukins/biosynthesis Leishmania major/growth & development,immunology Leishmaniasis, Cutaneous/immunology,microbiology Macrophages/immunology Mice Mice, Inbred BALB C Mice, Inbred C3H Mice, Inbred C57BL Molecular Sequence Data Polymerase Chain Reaction RNA, Messenger/genetics Transcription, Genetic
Chemicals
Cytokines DNA Primers Interleukins RNA, Messenger Interleukin-12 Interleukin-4
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Reiner S L
Department of Medicine, University of California, San Francisco 94143.
Zheng S
Wang Z E
Stowring L
Locksley R M
References (63)
63 references, click to expand
  1. Developmental modification of lipophosphoglycan during the differentiation of Leishmania major promastigotes to an infectious stage.
    EMBO J. 1992 Oct;11(10):3593-600 PMID: 1396559
  2. IL-4 directs the development of Th2-like helper effectors.
    J Immunol. 1990 Dec 1;145(11):3796-806 PMID: 2147202
  3. Changes in the precursor frequencies of IL-4 and IFN-gamma secreting CD4+ cells correlate with resolution of lesions in murine cutaneous leishmaniasis.
    J Immunol. 1992 Oct 15;149(8):2715-21 PMID: 1357029
  4. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice.
    J Exp Med. 1992 Oct 1;176(4):1091-8 PMID: 1328464
  5. Interleukin 4 is localized to and released by human mast cells.
    J Exp Med. 1992 Nov 1;176(5):1381-6 PMID: 1402683
  6. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells.
    J Exp Med. 1992 Nov 1;176(5):1387-98 PMID: 1357073
  7. Persistence of virulent Leishmania major in murine cutaneous leishmaniasis: a possible hazard for the host.
    Infect Immun. 1993 Jan;61(1):220-6 PMID: 8093358
  8. Patterns of cytokine secretion in murine leishmaniasis: correlation with disease progression or resolution.
    Infect Immun. 1990 Dec;58(12):3863-70 PMID: 2123823
  9. Murine Th1 and Th2 clones proliferate optimally in response to distinct antigen-presenting cell populations.
    J Immunol. 1991 Mar 15;146(6):1750-8 PMID: 1826010
  10. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers.
    J Exp Med. 1991 Apr 1;173(4):869-79 PMID: 1672545
  11. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells.
    J Immunol. 1991 May 1;146(9):3074-81 PMID: 1673147
  12. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor.
    Proc Natl Acad Sci U S A. 1991 May 15;88(10):4143-7 PMID: 1674604
  13. Production of interferon gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis.
    Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7011-5 PMID: 1908085
  14. IFN-gamma modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis.
    J Immunol. 1991 Nov 1;147(9):3149-55 PMID: 1833466
  15. Transcriptional regulation of cytokine genes in nontransformed T cells. Apparent constitutive signals in run-on assays can be caused by repeat sequences.
    J Immunol. 1991 Nov 15;147(10):3601-9 PMID: 1940359
  16. Macrophage deactivation by interleukin 10.
    J Exp Med. 1991 Dec 1;174(6):1549-55 PMID: 1744584
  17. IL-4 induces a Th2 response in Leishmania major-infected mice.
    J Immunol. 1992 Feb 15;148(4):1182-7 PMID: 1531351
  18. Cloning and expression of murine IL-12.
    J Immunol. 1992 Jun 1;148(11):3433-40 PMID: 1350290
  19. IL-10 synergizes with IL-4 and transforming growth factor-beta to inhibit macrophage cytotoxic activity.
    J Immunol. 1992 Jun 1;148(11):3578-82 PMID: 1588047
  20. IL-4 plays a dominant role in the differential development of Tho into Th1 and Th2 cells.
    J Immunol. 1992 Jun 15;148(12):3820-9 PMID: 1534825
  21. Stage-specific adhesion of Leishmania promastigotes to the sandfly midgut.
    Science. 1992 Jun 26;256(5065):1812-5 PMID: 1615326
  22. Recombinant interleukin-12 suppresses the synthesis of immunoglobulin E by interleukin-4 stimulated human lymphocytes.
    J Clin Invest. 1992 Jul;90(1):262-6 PMID: 1353081
  23. Transforming growth factor-beta in leishmanial infection: a parasite escape mechanism.
    Science. 1992 Jul 24;257(5069):545-8 PMID: 1636092
  24. Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation.
    Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8676-80 PMID: 1528880
  25. CD4+ subset expression in murine candidiasis. Th responses correlate directly with genetically determined susceptibility or vaccine-induced resistance.
    J Immunol. 1993 Feb 1;150(3):925-31 PMID: 8093707
  26. Activation of cytokine genes in T cells during primary and secondary murine influenza pneumonia.
    J Exp Med. 1993 Feb 1;177(2):475-82 PMID: 8426116
  27. TH1 and TH2 cell antigen receptors in experimental leishmaniasis.
    Science. 1993 Mar 5;259(5100):1457-60 PMID: 8451641
  28. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells.
    J Exp Med. 1993 Apr 1;177(4):1199-204 PMID: 8096238
  29. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses.
    Nature. 1993 Mar 18;362(6417):248-50 PMID: 8096327
  30. IL-2 is necessary for the progression of leishmaniasis in susceptible murine hosts.
    J Immunol. 1993 May 1;150(9):3924-31 PMID: 8473741
  31. 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):3725-9 PMID: 8097322
  32. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells.
    Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3730-4 PMID: 8097323
  33. Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function.
    Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3735-9 PMID: 8097324
  34. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages.
    Science. 1993 Apr 23;260(5107):547-9 PMID: 8097338
  35. Recombinant interleukin 12 cures mice infected with Leishmania major.
    J Exp Med. 1993 May 1;177(5):1505-9 PMID: 8097524
  36. Functional CD4 T cell subset interplay in an intact immune system.
    J Immunol. 1993 May 15;150(10):4270-6 PMID: 8097751
  37. Transfected Leishmania expressing biologically active IFN-gamma.
    J Immunol. 1993 Jun 1;150(11):5059-69 PMID: 8098724
  38. Interleukin 12 in host defense against microbial pathogens.
    Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5879-80 PMID: 8100997
  39. IL-4 inhibits H2O2 production and antileishmanial capacity of human cultured monocytes mediated by IFN-gamma.
    J Immunol. 1989 Nov 1;143(9):3020-4 PMID: 2509562
  40. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response.
    J Exp Med. 1993 Jun 1;177(6):1797-802 PMID: 8098733
  41. Interleukin 4 suppresses interleukin 2 and interferon gamma production by naive T cells stimulated by accessory cell-dependent receptor engagement.
    Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5914-8 PMID: 8100998
  42. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice.
    J Exp Med. 1993 Aug 1;178(2):567-77 PMID: 8101861
  43. Immunological regulation of experimental cutaneous leishmaniasis. IV. Prophylactic effect of sublethal irradiation as a result of abrogation of suppressor T cell generation in mice genetically susceptible to Leishmania tropica.
    J Exp Med. 1981 Mar 1;153(3):557-68 PMID: 6454739
  44. Systemic infection of Leishmania tropica (major) in various strains of mice.
    Trans R Soc Trop Med Hyg. 1981;75(6):851-4 PMID: 7330948
  45. Cell-mediated immune response in experimental visceral leishmaniasis. II. Oxygen-dependent killing of intracellular Leishmania donovani amastigotes.
    J Immunol. 1982 Jul;129(1):351-7 PMID: 6282967
  46. A method for the derivation and continuous propagation of cloned murine bone marrow macrophages.
    J Immunol Methods. 1983 Dec 30;65(3):319-32 PMID: 6655248
  47. Therapeutic effect of anti-L3T4 monoclonal antibody GK1.5 on cutaneous leishmaniasis in genetically-susceptible BALB/c mice.
    J Immunol. 1985 Sep;135(3):2108-14 PMID: 3926895
  48. Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators.
    Proc Natl Acad Sci U S A. 1986 Mar;83(6):1670-4 PMID: 2419912
  49. Cellular and humoral immunity to Leishmania major in genetically susceptible mice after in vivo depletion of L3T4+ T cells.
    J Immunol. 1987 Aug 15;139(4):1303-9 PMID: 3112230
  50. The generation of infective stage Leishmania major promastigotes is associated with the cell-surface expression and release of a developmentally regulated glycolipid.
    J Immunol. 1987 Nov 1;139(9):3099-106 PMID: 3312412
  51. 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):1675-84 PMID: 2903212
  52. CR3 (CD11b/CD18) expresses one binding site for Arg-Gly-Asp-containing peptides and a second site for bacterial lipopolysaccharide.
    J Exp Med. 1989 Jan 1;169(1):175-83 PMID: 2462607
  53. Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major.
    J Immunol. 1989 Jul 1;143(1):266-74 PMID: 2499629
  54. A new murine CD4+ T cell subset with an unrestricted cytokine profile.
    J Immunol. 1989 Jul 15;143(2):518-25 PMID: 2472442
  55. CR1, the C3b receptor, mediates binding of infective Leishmania major metacyclic promastigotes to human macrophages.
    J Immunol. 1989 Jul 15;143(2):617-22 PMID: 2525590
  56. The biology of the SCID mutation.
    Immunol Today. 1989 Oct;10(10):322-5 PMID: 2519515
  57. 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):115-27 PMID: 2104918
  58. Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine.
    J Immunol. 1990 Jun 15;144(12):4794-7 PMID: 2351828
  59. IL-4 production by T cells from naive donors. IL-2 is required for IL-4 production.
    J Immunol. 1990 Aug 15;145(4):1127-36 PMID: 2143207
  60. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells.
    J Exp Med. 1990 Sep 1;172(3):921-9 PMID: 2117636
  61. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein.
    Science. 1990 Sep 21;249(4975):1431-3 PMID: 1698311
  62. Resistance to murine cutaneous leishmaniasis is mediated by TH1 cells, but disease-promoting CD4+ cells are different from TH2 cells.
    Eur J Immunol. 1990 Sep;20(9):2067-74 PMID: 1976523
  63. Laminin on Toxoplasma gondii mediates parasite binding to the beta 1 integrin receptor alpha 6 beta 1 on human foreskin fibroblasts and Chinese hamster ovary cells.
    Infect Immun. 1992 Nov;60(11):4925-31 PMID: 1399003
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.179.2.447
Published
1994-02-01
Pages
447-56
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2191353
Subset
IM
Grants
NIAID NIH HHS · AI-30663 · United States
External Links
PubMed source DOI: 10.1084/jem.179.2.447 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2