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. 1980 Dec 1;152(6):1659–1669. doi: 10.1084/jem.152.6.1659

Activation of macrophages for enhanced release of superoxide anion and greater killing of Candida albicans by injection of muramyl dipeptide

PMCID: PMC2186025  PMID: 6256464

Abstract

The adjuvant muramyl dipeptide (MDP) has been shown to affect a number of macrophage functions in vitro. We studied the effect of subcutaneous injection of MDP into mice. Cultured peritoneal macrophages from treated mice displayed increased spreading, total cell protein, and specific activity of beta-glucosaminidase a constituent of macrophage lysosomes, and of lactate dehydrogenase. Generation of superoxide anion (O2-) by MDP-treated macrophages stimulated by contact with phorbol myristate acetate was enhanced by over fivefold to levels achieved by macrophages from bacillus Calmette-Guerin-infected mice. The enhancement in stimulated O2- release was noted by 1 h after injection of MDP, peaked by 3 h, and remained high for at least 48 h. Priming for enhancement of O2- release by MDP was similar in athymic nude mice and in normal littermates, suggesting that mature T lymphocytes are not involved in this MDP effect. Priming for enhanced stimulated O2- release, and morphologic and enzymic changes, were not achieved by injection of the D-D stereoisomer of MDP. Phagocytosis of Candida albicans was only slightly greater by macrophages from mice give MDP, but MDP-stimulated cells killed two times more C. albicans in vitro than did cells from untreated animals. When MDP was given 18 h before, simultaneously with, or 24 h after lethal infectious challenge with C. albicans, treated mice were protected compared with controls. These results suggest that injection of MDP effectively and rapidly activates macrophages in the recipient animal. This agent should serve as an important probe of macrophage physiology and, perhaps ultimately, as a means of enhancing host defense in humans.

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Selected References

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  1. Chedid L., Audibert F., Johnson A. G. Biological activities of muramyl dipeptide, a synthetic glycopeptide analogous to bacterial immunoregulating agents. Prog Allergy. 1978;25:63–105. [PubMed] [Google Scholar]
  2. Chedid L., Parant M., Parant F., Audibert F., Lefrancier F., Choay J., Sela M. Enhancement of certain biological activities of muramyl dipeptide derivatives after conjugation to a multi-poly(DL-alanine)--poly(L-lysine) carrier. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6557–6561. doi: 10.1073/pnas.76.12.6557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cohn Z. A. Activation of mononuclear phagocytes: fact, fancy, and future. J Immunol. 1978 Sep;121(3):813–816. [PubMed] [Google Scholar]
  4. Dinarello C. A., Elin R. J., Chedid L., Wolff S. M. The pyrogenicity of the synthetic adjuvant muramyl dipeptide and two structural analogues. J Infect Dis. 1978 Dec;138(6):760–767. doi: 10.1093/infdis/138.6.760. [DOI] [PubMed] [Google Scholar]
  5. Ellouz F., Adam A., Ciorbaru R., Lederer E. Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Commun. 1974 Aug 19;59(4):1317–1325. doi: 10.1016/0006-291x(74)90458-6. [DOI] [PubMed] [Google Scholar]
  6. Finger H., Wirsing von König C. H. Failure of synthetic muramyl dipeptide to increase antibacterial resistance. Infect Immun. 1980 Feb;27(2):288–291. doi: 10.1128/iai.27.2.288-291.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Johnston R. B., Jr, Godzik C. A., Cohn Z. A. Increased superoxide anion production by immunologically activated and chemically elicited macrophages. J Exp Med. 1978 Jul 1;148(1):115–127. doi: 10.1084/jem.148.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Juy D., Chedid L. Comparison between macrophage activation and enhancement of nonspecific resistance to tumors by mycobacterial immunoadjuvants. Proc Natl Acad Sci U S A. 1975 Oct;72(10):4105–4109. doi: 10.1073/pnas.72.10.4105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kireszenbaum F., Ferraresi R. W. Enhancement of host resistance against Trypanosoma cruzi infection by the immunoregulatory agent muramyl dipeptide. Infect Immun. 1979 Jul;25(1):273–278. doi: 10.1128/iai.25.1.273-278.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kohashi O., Kotani S., Shiba T., Ozawa A. Synergistic effect of polyriboinosinic acid:polyribocytidylic acid and either bacterial peptidoglycans or synthetic N-acetylmuramyl peptides on production of adjuvant-induced arthritis in rats. Infect Immun. 1979 Nov;26(2):690–697. doi: 10.1128/iai.26.2.690-697.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kotani S., Watanabe Y., Kinoshita F., Shimono T., Morisaki I. Immunoadjuvant activities of synthetic N-acetyl-muramyl-peptides or -amino acids. Biken J. 1975 Jun;18(2):105–111. [PubMed] [Google Scholar]
  12. Lehrer R. I., Ferrari L. G., Patterson-Delafield J., Sorrell T. Fungicidal activity of rabbit alveolar and peritoneal macrophages against Candida albicans. Infect Immun. 1980 Jun;28(3):1001–1008. doi: 10.1128/iai.28.3.1001-1008.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lehrer R. I. The fungicidal mechanisms of human monocytes. I. Evidence for myeloperoxidase-linked and myeloperoxidase-independent candidacidal mechanisms. J Clin Invest. 1975 Feb;55(2):338–346. doi: 10.1172/JCI107937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McCarthy K., Henson P. M. Induction of lysosomal enzyme secretion by alveolar macrophages in response to the purified complement fragments C5a and C5a des-arg. J Immunol. 1979 Dec;123(6):2511–2517. [PubMed] [Google Scholar]
  15. McLaughlin C. A., Schwartzman S. M., Horner B. L., Jones G. H., Moffatt J. G., Nestor J. J., Jr, Tegg D. Regression of tumors in guinea pigs after treatment with synthetic muramyl dipeptides and trehalose dimycolate. Science. 1980 Apr 25;208(4442):415–416. doi: 10.1126/science.7189295. [DOI] [PubMed] [Google Scholar]
  16. Murray H. W., Juangbhanich C. W., Nathan C. F., Cohn Z. A. Macrophage oxygen-dependent antimicrobial activity. II. The role of oxygen intermediates. J Exp Med. 1979 Oct 1;150(4):950–964. doi: 10.1084/jem.150.4.950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nagao S., Tanaka A., Yamamoto Y., Koga T., Onoue K., Shiba T., Kusumoto K., Kotani S. Inhibition of macrophage migration by muramyl peptides. Infect Immun. 1979 May;24(2):308–312. doi: 10.1128/iai.24.2.308-312.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nathan C. F., Root R. K. Hydrogen peroxide release from mouse peritoneal macrophages: dependence on sequential activation and triggering. J Exp Med. 1977 Dec 1;146(6):1648–1662. doi: 10.1084/jem.146.6.1648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nathan C., Nogueira N., Juangbhanich C., Ellis J., Cohn Z. Activation of macrophages in vivo and in vitro. Correlation between hydrogen peroxide release and killing of Trypanosoma cruzi. J Exp Med. 1979 May 1;149(5):1056–1068. doi: 10.1084/jem.149.5.1056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. North R. J. The concept of the activated macrophage. J Immunol. 1978 Sep;121(3):806–809. [PMC free article] [PubMed] [Google Scholar]
  21. Oppenheim J. J., Togawa A., Chedid L., Mizel S. Components of mycobacteria and muramyl dipeptide with adjuvant activity induce lymphocyte activating factor. Cell Immunol. 1980 Mar 1;50(1):71–81. doi: 10.1016/0008-8749(80)90007-6. [DOI] [PubMed] [Google Scholar]
  22. Pabst M. J., Johnston R. B., Jr Increased production of superoxide anion by macrophages exposed in vitro to muramyl dipeptide or lipopolysaccharide. J Exp Med. 1980 Jan 1;151(1):101–114. doi: 10.1084/jem.151.1.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Parant M., Parant F., Chedid L. Enhancement of the neonate's nonspecific immunity to Klebsiella infection by muramyl dipeptide, a synthetic immunoadjuvant. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3395–3399. doi: 10.1073/pnas.75.7.3395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Polhill R. B., Jr, Pruitt K. M., Johnston R. B., Jr Kinetic assessment of alternative complement pathway activity in a hemolytic system. I. Experimental and mathematical analyses. J Immunol. 1978 Jul;121(1):363–370. [PubMed] [Google Scholar]
  25. Sasada M., Johnston R. B., Jr Macrophage microbicidal activity. Correlation between phagocytosis-associated oxidative metabolism and the killing of Candida by macrophages. J Exp Med. 1980 Jul 1;152(1):85–98. doi: 10.1084/jem.152.1.85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schnyder J., Baggiolini M. Secretion of lysosomal hydrolases by stimulated and nonstimulated macrophages. J Exp Med. 1978 Aug 1;148(2):435–450. doi: 10.1084/jem.148.2.435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Takada H., Tsujimoto M., Kato K., Kotani S., Kusumoto S., Inage M., Shiba T., Yano I., Kawata S., Yokogawa K. Macrophage activation by bacterial cell walls and related synthetic compounds. Infect Immun. 1979 Jul;25(1):48–53. doi: 10.1128/iai.25.1.48-53.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tanaka A., Nagao S., Nagao R., Kotani S., Shiba T., Kusumoto S. Stimulation of the reticuloendothelial system of mice by muramyl dipeptide. Infect Immun. 1979 May;24(2):302–307. doi: 10.1128/iai.24.2.302-307.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Taniyama T., Holden H. T. Direct augmentation of cytolytic activity of tumor-derived macrophages and macrophage cell lines by muramyl dipeptide. Cell Immunol. 1979 Dec;48(2):369–374. doi: 10.1016/0008-8749(79)90131-x. [DOI] [PubMed] [Google Scholar]
  30. Wahl S. M., Wahl L. M., McCarthy J. B., Chedid L., Mergenhagen S. E. Macrophage activation by mycobacterial water soluble compounds and synthetic muramyl dipeptide. J Immunol. 1979 Jun;122(6):2226–2231. [PubMed] [Google Scholar]
  31. Wilson C. B., Tsai V., Remington J. S. Failure to trigger the oxidative metabolic burst by normal macrophages: possible mechanism for survival of intracellular pathogens. J Exp Med. 1980 Feb 1;151(2):328–346. doi: 10.1084/jem.151.2.328. [DOI] [PMC free article] [PubMed] [Google Scholar]

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