Abstract
Bacterial lipopolysaccharide (LPS) is generally regarded as one of the most potent macrophage activators. Thus, LPS has been used as an obligatory second signal to stimulate macrophage cytotoxic function against a wide array of bacterial and neoplastic targets. In this study, however, we define conditions under which LPS can suppress the development of cytotoxic function in normal human peripheral blood monocytes. When monocytes were treated with a priming dose of gamma interferon (γ-INF), followed 18–24 hr later by a triggering dose of LPS, significant cytotoxic function developed. However, when monocytes were treated with even minimal amounts of LPS during priming with interferon, the development of cytotoxic function following stimulation with a second, triggering dose of LPS was virtually abolished. This effect could be produced from 0 to 14 hr following the addition of γ-INF. The inhibition of monocyte cytotoxicity which was produced by LPS treatment during priming was dose dependent and could not be overcome by modifying either the priming dose of γ-IFN or the triggering dose of LPS. The suppression was largely overcome, however, by treatment with the cyclooxygenase inhibitor, indomethacin. The possibility that LPS-induced suppression of monocyte cytotoxicity was mediated by products of the cyclooxygenase pathway was supported further in this study by demonstrating that LPS stimulated the production of significant amounts of prostaglandin E2 (PGE2) from monocytes and that this was facilitated by γ-IFN. In kinetics studies, it appeared that LPS suppression of monocyte activation was correlated temporally with a heightened sensitivity to suppression by exogenously added PGE2, a condition which was reduced greatly by the end of the priming phase. These results demonstrate that the prototypical macrophage activator, LPS, can, under defined conditions, suppress rather than enhance the development of macrophage cytotoxic function. They suggest that chronic exposure to LPS during Gram-negative infections may actually impair the ability of monocytes to become activated.
Similar content being viewed by others
References
Jawetz E, Melnick JL, Adelberg EA (eds). Cell structure.In Review of Medical Microbiology. Los Altos, Lange Medical, 1978, pp 5–28
Couturier C, Haeffner-Cavaillon N, Caroff M, Kazatchkine MD: Binding sites for endotoxins (lipopolysaccharides) on human monocytes. J Immunol 147:1899–1904, 1991
Weiner E, Beck A, Shilo M: Effect of bacterial lipopolysaccharides on mouse peritoneal leukocytes. Lab Invest 14:475–487, 1965
Hammerstrom J, Unsgaard G: In vitro influence of endotoxin on human mononuclear phagocyte structure and function. I. Depression of protein synthesis, phagocytosis of Candida albicans and induction of cytostatic activity. Acta Pathol Microbiol Scand Sect C 87:381–389, 1979
Cooper PH, Mayer P, Baggiolini M: Stimulation of phagocytosis in bone marrow-derived mouse macrophages by bacterial lipopolysaccharide: Correlation with biochemical and functional parameters. J Immunol 133(2):913–922, 1984
Kaku M, Yagawa K, Nagao S, Tanaka A: Enhanced superoxide anion release from phagocytes by muramyl dipeptide or lipopolysaccharide. Infect Immun 39(2):559–564, 1983
Ding AH, Nathan CF: Trace levels of bacterial lipopolysaccharide prevent interferon-γ or tumor necrosis factor-α from enhancing mouse peritoneal macrophage respiratory burst capacity. J Immunol 139(6):1971–1977, 1987
Rellstab P, Schaffner A: Endotoxin suppresses the generation of O −2 and H2O2 by “resting” and lymphokine-activated human blood-derived macrophages. J Immunol 142:2813–2820, 1989
Humes JL, Sadowski S, Galavage M, Goldenberg M, Subers E, Bonney RJ, Kuehl FA Jr: Evidence for two sources of arachidonic acid for oxidative metabolism by mouse peritoneal macrophages. J Biol Chem 257:1591–1594, 1982
Leslie CC, Detty DM: Arachidonic acid turnover in response to lipopolysaccharide and opsonized zymosan in human monocyte-derived macrophages. Biochem J 236(1):251–259, 1986
Nichols FC, Schenkein HA, Rutherford RB: Prostaglandin E2, prostaglandin E1 and thromboxane B2 release from human monocytes treated with C3b or bacterial lipopolysaccharide. Biochim Biophys Acta 927(2):149–157, 1987
Fu JY, Masferrer JL, Seibert K, Raz A, Needleman P: The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem 265(28):16737–16740, 1990
Meltzer MS: Macrophage activation for tumor cytotoxicity: Characterization of priming and trigger signals during lymphokine activation. J Immunol 127:179–183, 1981
Meltzer MS: Tumor cytotoxicity by lymphokine-activated macrophages: Development of macrophage tumoricidal activity requires a sequence of reaction. Lymphokines 3:319–343, 1981
Russell SW, Pace JL: Both the kind and magnitude of stimulus are important in overcoming the negative regulation of macrophage activation by PGE2. J Leukoc Biol 35:291–301, 1984
Chen TY, Bright SW, Pace JL, Russell SW, Morrison DC: Induction of macrophage-mediated tumor cytotoxicity by a hamster monoclonal antibody with specificity for lipopolysaccharide receptor. J Immunol 145(1):8–12, 1990
Kalafut F, Kusenda J, Klobusika M, Novotna L: In vitro activation of tumoricidal properties of rat peritoneal macrophages using lipopolysaccharide. Neoplasma 37(4):405–414, 1990
Lorence RM, Edwards CK, Walter RJ, Kelley KW, Greager JA: In vivo effects of recombinant interferon-gamma: Augmentation of endotoxin-induced necrosis of tumors and priming of macrophages for tumor necrosis factor-alpha production. Cancer Lett 52:223–229, 1990
Russell SW, Doe WF, McIntosh AT: Functional characterization of a stable, noncytolytic stage of macrophage activation in tumors. J Exp Med 146(6):1511–1520, 1977
Hibbs JB, Taintor RR, Chapman HA, Weinberg JB: Macrophage tumor killing: Influence of the local environment. Science 197(4300):279–282, 1977
Haslberger A, Sayers T, Reiter H, Chung J, Schütze E: Reduced release of TNF and PCA from macrophages of tolerant mice. Circ Shock 26:185–192, 1988
Simpson S, Modi M, Balk R, Bone R, Casey L: Reduced alveolar macrophage production of tumor necrosis factor during sepsis in mice and man. Crit Care Med 19(8):1060–1066, 1990
Braun DP, Harris JE: Relationship of leukocyte numbers, immunoregulatory cell function, and phytohemagglutinin responsiveness in cancer patients. J Natl Cancer Inst 67:809–814, 1981
Braun DP, Siziopikou KP, Casey LC, Harris JE: The in vitro development of cytotoxicity in response to granulocyte/macrophage-colony-stimulating factor or interferon-γ in the peripheral blood monocytes of patients with solid tumors: Modulation by arachidonic acid metabolic inhibitors. Cancer Immunol Immunother 32:55–61, 1990
Siziopikou KP, Harris JE, Casey LC, Nawas Y, Braun DP: Impaired tumoricidal function of alveolar macrophages from patients with non-small cell lung cancer. Cancer 68:1035–1044, 1991
Prpic V, Weiel JE, Somers SD, DiGuiseppi J, Gonias SL, Pizzo SV, Hamilton TA, Herman B, Adams DO: Effects of bacterial lipopolysaccharide on the hydrolysis of phosphatidylinositol-4,5-bisphosphate in murine peritoneal macrophages. J Immunol 139(2):526–533, 1987
Old LJ: Tumor necrosis factor (TNF). Science 230:630–632, 1985
Urban JL, Shepard HM, Rothstein JL, Sugarman BJ, Schreiber H: Tumor necrosis factor: A potent effector molecule for tumor cell killing by activated macrophages. Proc Natl Acad Sci USA 83:5233–5237, 1986
Adams DO, Kao KJ, Farb R, Pizzo SV: Effector mechanisms of cytolytically activated macrophages II. Secretion of a cytolytic factor by activated macrophages and its relationship to secreted Neutral proteases. J Immunol 124:293–300, 1980
Lovett D, Kozan B, Hadan M, Resch K, Gemsa D: Macrophage cytotoxicity: IL-1 as a mediator of tumor cytostasis. J Immunol 136(1):340–347, 1986
Virca GD, Kim SY, Glaser KB, Vlevitch RJ: Lipopolysaccharide induces hyporesponsiveness to its own action in RAW 264.7 cells. J Biol Chem 264(36):21951–21956, 1989
Sherr CJ: Colony-stimulating factor-I receptor. Blood 75(1):1–12, 1990
Schleiffenbaum B, Fehr J: The tumor necrosis factor receptor and human neutrophil function. Deactivation and cross-deactivation of tumor necrosis factor-induced neutrophil responses by receptor down-regulation. J Clin Invest 86(1):184–195, 1990
Conover CA, Powell DR: Insulin-like growth factor (IGFI-binding protein-3 blocks IGF-1-induced receptor down-regulation and cell desensitization in cultured bovine fibroblasts. Endocrinology 129(2):710–716, 1991
Schultz RM, Pavlidis NA, Stylos WA, Chirigos MA: Regulation of macrophage tumoricidal function: A role for prostaglandins of the E series. Science 202(4365):320–321, 1978
Taffet SM, Russell SW: Macrophage-mediated tumor cell killing: Regulation of expression of cytolytic activity by prostaglandin E. J Immunol 126(2):424–427, 1981
Sibley LD, Hunter SW, Brennan PJ, Krahenbuhl JL: Mycobacterial Lipoarabinomannan inhibits gamma interferon-mediated activation of macrophages. Infect Immun 56(5):1232–1236, 1988
Sibley LD, Krahenbuhl JL: Induction of unresponsiveness to gamma interferon in macrophages infected with Mycobacterium leprae. Infect Immun 56(8):1912–1919, 1988
Remold-O'Donnell E, Alpert HR: Alternation of hormone-stimulated cyclic AMP synthesis in guinea pig peritoneal macrophages. Cell Immunol 45:221–229, 1979
Monick M, Glazier J, Hunninghake GW: Human alveolar macrophages suppress interleukin-1 (IL-1) activity via the secretion of prostaglandin E2. Am Rev Resp Dis 135:72–78, 1987
Kunkel SL, Spengler M, May MA, Spengler R, Larrick J, Remick D: Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression. J Biol Chem 263(11):5380–5384, 1988
Utsugi T, Fidler IJ: Prostaglandin E2 does not inhibit tumoricidal activity of mouse macrophages against adherent tumor cells. J Immunol 146(6):2066–2071, 1991
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Chu, E., Casey, L.C., Harris, J.E. et al. Suppression of the development of tumoricidal function in gamma interferon-treated human peripheral blood monocytes by lipopolysaccharide: The role of cyclooxygenase metabolites. J Clin Immunol 13, 49–57 (1993). https://doi.org/10.1007/BF00920635
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00920635