Synthetic muramyldipeptide (MDP), the minimum structural moiety of bacterial peptidoglycan for adjuvant and related activities, sensitized mice for two types of lethal shock induced by lipopolysaccharide (LPS): an early anaphylactoid shock and late endotoxin shock. In relation to the late reaction in MDP-primed mice, enhanced production of inflammatory cytokines was induced in response to various bacterial components. MDP showed a priming effect in mice not only when administered parentally but also via the oral route. MDP activated human monocytic THP-1 cells in a CD14-, Toll-like receptor 2 (TLR2)- and TLR4-independent manner to increase expression of MyD88, a common adaptor and signaling molecule for TLRs, and exhibited synergistic cytokine-inducing effects with TLR4 agonists (LPS, synthetic lipid A), TLR2 agonist (synthetic lipopeptide), and TLR9 agonist (bacterial CpG DNA) in THP-1 cells in culture. Consistent with these findings, MDP primed TLR2 knockout mice as well as wild-type controls, but not TLR4-mutated C3H/HeJ mice, to enhance production of tumor necrosis factor-α upon stimulation with synthetic lipid A. In contrast to the BCG- and Propionibacterium acnes-priming system, MDP primed mice in an interferon-γ-independent manner. Further studies are required to elucidate the mechanisms of the synthetic and priming activities of MDP for various bacterial components.
References
1.
Ribi EE, Cantrell JL, Von Eschen KB, Schwartzman SMEnhancement of endotoxic shock by N-acetylmuramyl-L-alanyl-(L-seryl)-D-isoglutamine (muramyl dipeptide). Cancer Res1979; 39: 4756—4759.
2.
Takada H., Kotani S.Immunopharmacological activities of synthetic muramyl-peptides. In: Stewart-Tull DES, Davies M. (eds) Immunology of the Bacterial Cell Envelope. Chichester: Wiley, 1985; 119—152.
3.
Takada H., Kotani S.Muramyl dipeptide and derivatives. In: Stewart-Tull DES. (ed) The Theory and Practical Application of Adjuvant . Chichester: Wiley, 1995; 171—202.
4.
Chedid LA, Parant MA, Audibert FM et al. Biological activity of a new synthetic muramyl peptide adjuvant devoid of pyrogenicity. Infect Immun1982; 35: 417—424.
5.
Bloksma N., Hofhuis Fma, Willers Jmn.Endotoxin-induced antitumor activity in the mouse is highly potentiated by muramyl dipeptide. Cancer Lett1984; 23: 159—165.
6.
Bloksma N., Hofhuis Fma, Willers Jmn.Muramyl dipeptide analogues as potentiators of the antitumor action of endotoxin . Cancer Immunol Immunother1985; 19: 205—210.
7.
Takada H., Galanos C.Enhancement of endotoxin lethality and generation of anaphylactoid reactions by lipopolysaccharides in muramyl-dipeptide-treated mice. Infect Immun1987; 55: 409—413.
8.
Takada H., Hirai H., Fujiwara T., Koga T., Ogawa T., Hamada S.Bacteroides lipopolysaccharides (LPS) induce anaphylactoid and lethal reactions in LPS-responsive and -nonresponsive mice primed with muramyl dipeptide. J Infect Dis1990; 162: 428—434.
9.
Endo Y., Shibazaki M., Nakamura M., Takada H.Contrasting effects of lipopolysaccharides (endotoxins) from oral black-pigmented bacteria and Enterobacteriaceae on platelets, a major source of serotonin, and on histamine-forming enzyme in mice. J Infect Dis1997; 175: 1404—1412.
10.
Shibazaki M. , Kawabata Y., Yokochi T., Nishida A., Takada H., Endo Y.Complement-dependent accumulation and degradation of platelets in the lung and liver induced by injection of lipopolysaccharides . Infect Immun1999; 67: 5186—5191.
11.
Kawabata Y. , Yang S., Yokochi T.et al.Complement system is involved in anaphylactoid reaction induced by lipopolysaccharides in muramyldipeptide-treated mice. Shock2000; 14: 572—577.
12.
Endo Y., Yokochi T., Matsushita M., Fujita T., Takada H.Complement-dependent platelet degradation and anaphylactoid shock in mice induced by lipopolysaccharide carrying the mannose homopolymer. J Endotoxin Res2001; 7: 451—455.
13.
Zhao L., Ohtaki Y., Yamaguchi K. et al. LPS-induced platelet response and rapid shock in mice: contribution of O-antigen region of LPS and involvement of the lectin pathway of the complement system. Blood2002; 100: 3233—3239.
14.
Kuper CF, Groeneveld Php, Bloksma N.In vivo effects of toxic and detoxified endotoxin alone or in combination with muramyl dipeptide on lymphoid and non-lymphoid cells in the spleen of Meth A sarcoma-bearing mice. Virchows Arch B 1986; 51: 341—351.
15.
Kuper CF, Bloksma N., Bruyntjes JP, Hofhuis MAQuantitative histology of muramyl dipeptide-potentiated induction of tumor necrosis factor by endotoxins. Virchows Arch B 1987; 53: 316—323.
16.
Tsujimoto M. , Kotani S., Shiba T. et al. Regressive action with induction of hemorrhagic necrosis of mixtures of acylated muramylpeptides and synthetic, low toxic lipid A analogs on Meth A fibrosarcoma. Adv Biosci1988; 68: 151—165.
17.
Parant MA, Pouillart P., Le Contel C, Parant FJ, Chedid LA, Bahr GMSelective modulation of lipopolysaccharide-induced death and cytokine production by various muramyl peptides. Infect Immun1995; 63: 110—115.
18.
Takada H., Kawabata Y., Arakaki R.et al.Molecular and structural requirements of lipoteichoic acid from Enterococcus hirae ATCC 9790 for cytokine-inducing, antitumor, and antigenic activties . Infect Immun1995; 63: 57—65.
19.
Monodane T. , Kawabata Y., Yang S., Hase S., Takada H.Induction of tumour necrosis factor-α and interleukin-6 in mice in vivo and in murine peritoneal macrophages and human whole blood cells in vitro by Micrococcus luteus teichuronic acids. J Med Microbiol2001; 50: 4—12.
20.
Takada H., Kawabata Y., Tamura M. et al. Cytokine induction by extracellular products of oral viridans group streptococci. Infect Immun1993; 61: 5252—5260.
21.
Isobe Y. `Streptococcus milleri' group bacteria induce anaphylactoid reaction and inflammatory cytokines in mice primed with muramyldipeptide [in Japanese] . J Dent Health1998; 48: 170—182.
22.
Yang S., Sugawara S., Monodane T. et al. Micrococcus luteus teichuronic acids activate human and murine monocytic cells in a CD14- and Toll-like receptor 4-dependent manner. Infect Immun2001; 69: 2025—2030.
23.
Takeuchi O. , Kaufmann A., Grote K. et al. Preferentially the S-stereoisomer of the mycoplasmal lipopeptidemacrophageactivating lipopeptide-2 activates immune cells through a Toll-like receptor 2- and MyD88-dependent signaling pathway . J Immunol2000; 164: 554—557.
24.
Underhill DM , Ozinsky A., Smith KD, Aderem A.Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages. Proc Natl Acad Sci USA1999; 96: 14459—14463.
25.
Means TK, Wang S., Lien E., Yoshimura A., Golenbock DT, Fenton MJHuman Toll-like receptors mediate cellular activation by Mycobacterium tuberculosis . J Immunol1999; 163: 3920—3927.
26.
Takeuchi O., Kawai T., Mühlradt PF et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol2001; 13: 933—940.
27.
Takeuchi O., Sato S., Horiuchi T. et al. Role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol2002; 169: 10—14.
28.
Takeuchi O., Hoshino K., Kawai T. et al. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity1999; 11: 443—451.
29.
Yang S., Tamai R., Akashi S. et al. Synergistic effect of muramyldipeptide with lipopolysaccharide or lipoteichoic acid to induce inflammatory cytokines in human monocytic cells in culture. Infect Immun2001; 69: 2045—2053.
30.
Nagai Y., Akashi S., Nagafuku M.et al.Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol2002; 3: 667—672.
31.
Sugiyama A., Arakaki R., Ohnishi T., Arakaki N., Daikuhara Y., Takada H.Lipoteichoic acid and interleukin 1 stimulate synergistically production of hepatocyte growth factor (scatter factor) in human gingival fibroblasts in culture. Infect Immun1996; 64: 1426—1431.
32.
Gao JJ, Xue Q., Zuvanich EG, Haghi K., Morrison DCCommertial preparations of lipoteichoic acid contain endotoxin that contributes to activation of mouse macrophages in vitro. Infect Immun2001; 69: 751—757.
33.
Morath S., Geyer A., Spreitzer I., Hermann C., Hartung T.Structural decomposition and heterogeneity of commercial lipoteichoic acid preparations. Infect Immun2002; 70: 938—944.
34.
Morath S., Stadelmaier A., Geyer A., Schmidt RR, Hartung T.Syntehtic lipoteichoic acid from Staphylococcus aureus is a potent stimulus of cytokine release. J Exp Med2002; 195: 1635—1640.
35.
Parant M., Parant F., Vinit M-A., Jupin C., Nose Y., Chedid L.Priming effect of muramyl peptides for induction by lipopolysaccharide of tumor necrosis factor production in mice. J Leukoc Biol1990; 47: 164—169.
36.
Le Contel C, Temime N., Charron DJ, Parant MAModulation of lipopolysaccharide-induced cytokine gene expression in mouse bone marrow-derived macrophages by muramyl dipeptide . J Immunol1993; 150: 4541—4549.
37.
Galanos C., Freudenberg MAMechanisms of endotoxin shock and endotoxin hypersensitivity. Immunobiology1993; 187: 346—356.
38.
Katschinski T., Galanos C., Coumbos A., Freudenberg MAGamma interferon mediates Propionibacterium acnes-induced hypersensitivity to lipopolysaccharide in mice. Infect Immun1992; 60: 1994—2001.
39.
Kamijo R., Le J., Shapiro D. et al. Mice that lack the interferon-γ receptor have profoundly altered responses to infection with Bacillus Calmette-Guérin and subsequent challenge with lipopolysaccharide. J Exp Med1993; 178: 1435—1440.
40.
Freudenberg MA, Kopf M., Galanos C.Lipopolysacharidesensitivity of interferon-γ receptor deficient mice. J Endotoxin Res1996 ; 3: 291—295.
41.
Beigneux A. , Huang J., Le Contel C, Heremans H., Parant MADifferential role of interferon-γ in the potentiating effect of muramyl peptides for enhanced responses to lipopolysaccharide in mice: effect of cyclosporin A. J Interferon Cytokine Res1995; 14: 359—365.
42.
Nagao S., Akagawa KS, Yamada K., Yagawa K., TokunagaT, Kotani S. Lack of response of murine peritoneal macrophages to in vitro activation by muramyl dipeptide (MDP). I. Macrophage activation by MDP is species dependent. Microbiol Immunol1990; 34: 323—335.
43.
Yoshimura A. , Takada H., Kaneko T., Kato I., Golenbock D., Hara Y.Structural requirements of muramylpeptides for induction of Toll-like receptor 2-mediated NK-# B activation in CHO cells . J Endotoxin Res2000; 6: 407—410.
44.
Vidal VF, Castéran N., Riendeau CJ et al. Macrophage stimulation with murabutide, an HIV-suppressive muramyl peptide derivative, selectively activates extracellular signal-regulated kinase 1 and 2, C/EBPβ and STAT1: role of CD14 and Toll-like receptors 2 and 4. Eur J Immunol2001; 31: 1962—1971.
45.
Tsuchida K. , Takemoto Y., Yamagami S.et al.Detection of peptidoglycan and endotoxin in dialysate, using silkworm larvae plasma and Limulus amebocyte lysate methods . Nephron1997; 75: 438—443.
46.
Kawai T., Adachi O., Ogawa T., Takeda K., Akira S.Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity1999; 11: 115—122.
47.
Takeuchi O. , Takeda K., Hoshino K., Adachi O., Ogawa T., Akira S.Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. Int Immunol2000; 12: 113—117.
48.
Kang D., Liu G., Lundström A., Gelius E., Steiner H.A peptidoglycan recognition protein in innate immunity conserved from insects to humans. Proc Natl Acad Sci USA1998; 95: 10078-10082.
