• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Aug 15, 1995; 92(17): 7804–7808.

The killing of Leishmania major by human macrophages is mediated by nitric oxide induced after ligation of the Fc epsilon RII/CD23 surface antigen.


Serum IgE concentrations and the expression of the low-affinity receptor for IgE (Fc epsilon RII/CD23) are increased in cutaneous leishmaniasis or after immune challenge with Leishmania antigens. In vitro, the ligation of CD23 by IgE-anti-IgE immune complexes (IgE-IC) or by anti-CD23 monoclonal antibody (mAb) induces nitric oxide (NO) synthase and the generation of various cytokines by human monocytes/macrophages. The present study shows that IgE-IC, via CD23 binding, induce intracellular killing of Leishmania major in human monocyte-derived macrophages through the induction of the L-arginine:NO pathway. This was demonstrated by increased generation of nitrite (NO2-), the stable oxidation product of NO, and by the ability of NG-monomethyl-L-arginine to block both NO generation and parasite killing. A similar NO-dependent effect was observed with interferon gamma-treated cells. Tumor necrosis factor alpha is involved in this process, since both the induction of NO synthase and the killing of parasites caused by anti-CD23 mAb were inhibited by an anti-tumor necrosis factor alpha mAb. Treatment of noninfected CD23+ macrophages with IgE-IC provided protection against subsequent in vitro infection of these cells by Leishmania major promastigotes. Thus, IgE-IC promote killing of L. major by inducing NO synthase in human macrophages.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.5M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Green SJ, Nacy CA, Meltzer MS. Cytokine-induced synthesis of nitrogen oxides in macrophages: a protective host response to Leishmania and other intracellular pathogens. J Leukoc Biol. 1991 Jul;50(1):93–103. [PubMed]
  • Rockett KA, Awburn MM, Cowden WB, Clark IA. Killing of Plasmodium falciparum in vitro by nitric oxide derivatives. Infect Immun. 1991 Sep;59(9):3280–3283. [PMC free article] [PubMed]
  • James SL, Glaven J. Macrophage cytotoxicity against schistosomula of Schistosoma mansoni involves arginine-dependent production of reactive nitrogen intermediates. J Immunol. 1989 Dec 15;143(12):4208–4212. [PubMed]
  • Muñoz-Fernández MA, Fernández MA, Fresno M. Activation of human macrophages for the killing of intracellular Trypanosoma cruzi by TNF-alpha and IFN-gamma through a nitric oxide-dependent mechanism. Immunol Lett. 1992 Jun;33(1):35–40. [PubMed]
  • Adams LB, Hibbs JB, Jr, Taintor RR, Krahenbuhl JL. Microbiostatic effect of murine-activated macrophages for Toxoplasma gondii. Role for synthesis of inorganic nitrogen oxides from L-arginine. J Immunol. 1990 Apr 1;144(7):2725–2729. [PubMed]
  • Stuehr DJ, Marletta MA. Induction of nitrite/nitrate synthesis in murine macrophages by BCG infection, lymphokines, or interferon-gamma. J Immunol. 1987 Jul 15;139(2):518–525. [PubMed]
  • Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993 Dec 30;329(27):2002–2012. [PubMed]
  • Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed]
  • Drapier JC, Wietzerbin J, Hibbs JB., Jr Interferon-gamma and tumor necrosis factor induce the L-arginine-dependent cytotoxic effector mechanism in murine macrophages. Eur J Immunol. 1988 Oct;18(10):1587–1592. [PubMed]
  • Cunha FQ, Weiser WY, David JR, Moss DW, Moncada S, Liew FY. Recombinant migration inhibitory factor induces nitric oxide synthase in murine macrophages. J Immunol. 1993 Mar 1;150(5):1908–1912. [PubMed]
  • Reed SG, Scott P. T-cell and cytokine responses in leishmaniasis. Curr Opin Immunol. 1993 Aug;5(4):524–531. [PubMed]
  • Nussler AK, Billiar TR. Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol. 1993 Aug;54(2):171–178. [PubMed]
  • Denis M. Tumor necrosis factor and granulocyte macrophage-colony stimulating factor stimulate human macrophages to restrict growth of virulent Mycobacterium avium and to kill avirulent M. avium: killing effector mechanism depends on the generation of reactive nitrogen intermediates. J Leukoc Biol. 1991 Apr;49(4):380–387. [PubMed]
  • Bukrinsky MI, Nottet HS, Schmidtmayerova H, Dubrovsky L, Flanagan CR, Mullins ME, Lipton SA, Gendelman HE. Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)-infected monocytes: implications for HIV-associated neurological disease. J Exp Med. 1995 Feb 1;181(2):735–745. [PMC free article] [PubMed]
  • De Maria R, Cifone MG, Trotta R, Rippo MR, Festuccia C, Santoni A, Testi R. Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors. J Exp Med. 1994 Nov 1;180(5):1999–2004. [PMC free article] [PubMed]
  • Reiling N, Ulmer AJ, Duchrow M, Ernst M, Flad HD, Hauschildt S. Nitric oxide synthase: mRNA expression of different isoforms in human monocytes/macrophages. Eur J Immunol. 1994 Aug;24(8):1941–1944. [PubMed]
  • Mossalayi MD, Paul-Eugène N, Ouaaz F, Arock M, Kolb JP, Kilchherr E, Debré P, Dugas B. Involvement of Fc epsilon RII/CD23 and L-arginine-dependent pathway in IgE-mediated stimulation of human monocyte functions. Int Immunol. 1994 Jul;6(7):931–934. [PubMed]
  • Arock M, Le Goff L, Bécherel PA, Dugas B, Debré P, Mossalayi MD. Involvement of Fc epsilon RII/CD23 and L-arginine dependent pathway in IgE-mediated activation of human eosinophils. Biochem Biophys Res Commun. 1994 Aug 30;203(1):265–271. [PubMed]
  • Ouaaz F, Sola B, Issaly F, Kolb JP, Davi F, Mentz F, Arock M, Paul-Eugène N, Körner M, Dugas B, et al. Growth arrest and terminal differentiation of leukemic myelomonocytic cells induced through ligation of surface CD23 antigen. Blood. 1994 Nov 1;84(9):3095–3104. [PubMed]
  • Bécherel PA, Mossalayi MD, Ouaaz F, Le Goff L, Dugas B, Paul-Eugène N, Frances C, Chosidow O, Kilchherr E, Guillosson JJ, et al. Involvement of cyclic AMP and nitric oxide in immunoglobulin E-dependent activation of Fc epsilon RII/CD23+ normal human keratinocytes. J Clin Invest. 1994 May;93(5):2275–2279. [PMC free article] [PubMed]
  • Delespesse G, Suter U, Mossalayi D, Bettler B, Sarfati M, Hofstetter H, Kilcherr E, Debre P, Dalloul A. Expression, structure, and function of the CD23 antigen. Adv Immunol. 1991;49:149–191. [PubMed]
  • Vouldoukis I, Issaly F, Fourcade C, Paul-Eugène N, Arock M, Kolb JP, da Silva OA, Monjour L, Poinsot H, Tselentis Y, et al. CD23 and IgE expression during the human immune response to cutaneous leishmaniasis: possible role in monocyte activation. Res Immunol. 1994 Jan;145(1):17–27. [PubMed]
  • Kolb JP, Paul-Eugene N, Damais C, Yamaoka K, Drapier JC, Dugas B. Interleukin-4 stimulates cGMP production by IFN-gamma-activated human monocytes. Involvement of the nitric oxide synthase pathway. J Biol Chem. 1994 Apr 1;269(13):9811–9816. [PubMed]
  • Mossalayi MD, Arock M, Delespesse G, Hofstetter H, Bettler B, Dalloul AH, Kilchherr E, Quaaz F, Debré P, Sarfati M. Cytokine effects of CD23 are mediated by an epitope distinct from the IgE binding site. EMBO J. 1992 Dec;11(12):4323–4328. [PMC free article] [PubMed]
  • Maurer D, Fiebiger E, Reininger B, Wolff-Winiski B, Jouvin MH, Kilgus O, Kinet JP, Stingl G. Expression of functional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals. J Exp Med. 1994 Feb 1;179(2):745–750. [PMC free article] [PubMed]
  • Severn A, Xu D, Doyle J, Leal LM, O'Donnell CA, Brett SJ, Moss DW, Liew FY. Pre-exposure of murine macrophages to lipopolysaccharide inhibits the induction of nitric oxide synthase and reduces leishmanicidal activity. Eur J Immunol. 1993 Jul;23(7):1711–1714. [PubMed]
  • Geller DA, Lowenstein CJ, Shapiro RA, Nussler AK, Di Silvio M, Wang SC, Nakayama DK, Simmons RL, Snyder SH, Billiar TR. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3491–3495. [PMC free article] [PubMed]
  • Mentz F, Ouaaz F, Michel A, Blanc C, Hervé P, Bismuth G, Debré P, Merle-Béral H, Mossalayi MD. Maturation of acute T-lymphoblastic leukemia cells after CD2 ligation and subsequent treatment with interleukin-2. Blood. 1994 Aug 15;84(4):1182–1192. [PubMed]
  • Hamid Q, Springall DR, Riveros-Moreno V, Chanez P, Howarth P, Redington A, Bousquet J, Godard P, Holgate S, Polak JM. Induction of nitric oxide synthase in asthma. Lancet. 1993 Dec 18;342(8886-8887):1510–1513. [PubMed]
  • Assreuy J, Cunha FQ, Epperlein M, Noronha-Dutra A, O'Donnell CA, Liew FY, Moncada S. Production of nitric oxide and superoxide by activated macrophages and killing of Leishmania major. Eur J Immunol. 1994 Mar;24(3):672–676. [PubMed]
  • Zwingenberger K, Harms G, Pedrosa C, Omena S, Sandkamp B, Neifer S. Determinants of the immune response in visceral leishmaniasis: evidence for predominance of endogenous interleukin 4 over interferon-gamma production. Clin Immunol Immunopathol. 1990 Nov;57(2):242–249. [PubMed]
  • Chartrain NA, Geller DA, Koty PP, Sitrin NF, Nussler AK, Hoffman EP, Billiar TR, Hutchinson NI, Mudgett JS. Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J Biol Chem. 1994 Mar 4;269(9):6765–6772. [PubMed]
  • Xie QW, Whisnant R, Nathan C. Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J Exp Med. 1993 Jun 1;177(6):1779–1784. [PMC free article] [PubMed]
  • Cifone MG, Festuccia C, Cironi L, Cavallo G, Chessa MA, Pensa V, Tubaro E, Santoni A. Induction of the nitric oxide-synthesizing pathway in fresh and interleukin 2-cultured rat natural killer cells. Cell Immunol. 1994 Aug;157(1):181–194. [PubMed]
  • Aubry JP, Pochon S, Graber P, Jansen KU, Bonnefoy JY. CD21 is a ligand for CD23 and regulates IgE production. Nature. 1992 Aug 6;358(6386):505–507. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • Gene
    Gene links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene links
  • MedGen
    Related information in MedGen
  • OMIM
    OMIM record citing PubMed
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links
  • Taxonomy
    Related taxonomy entry
  • Taxonomy Tree
    Taxonomy Tree

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...