Abstract
Toxic shock syndrome toxin 1 (TSST-1) is a Mr 22,000 protein produced by Staphylococcus aureus. It is thought to be the cause of toxic shock syndrome. We investigated the hypothesis that TSST-1 induces nitric oxide (NO) synthase and that the NO formed may be involved in the pathogenesis of toxic shock syndrome. We used the murine monocyte-macrophage cell line J744.2 that responds to TSST-1 and also expresses NO synthase activity upon immunological stimulation. J774.2 macrophages stimulated with TSST-1 (10-100 nM) generated nitrite, a breakdown product of NO, and induced concentration-dependent elevations of cGMP in the pig kidney epithelial cell line (LLC-PK1). This latter effect was due to the generation of L-arginine-derived NO for it was (i) abolished by oxyhemoglobin (10 microM), a scavenger of NO, or by methylene blue (10 microM), an inhibitor of NO-activated guanylate cyclase; (ii) potentiated by superoxide dismutase (100 units/ml), which prolongs the life of NO; (iii) inhibited by NG-monomethyl-L-arginine (0.3 mM), an inhibitor of NO synthase; (iv) significantly decreased when L-arginine (0.4 mM) in the medium was replaced by D-arginine (0.4 mM). Moreover, TSST-1 (100 nM) enhanced the activity of cytosolic NO synthase in J774.2 cells. Hydrocortisone (1 microM) but not indomethacin (5 micrograms/ml) or salicylic acid (5 micrograms/ml) prevented the generation of NO2- and the increases in cGMP levels in LLC-PK1 cells induced by J774.2 cells stimulated with TSST-1. The effects of hydrocortisone were partially reversed by coincubation with RU 486 (1 microM), an antagonist of glucocorticoid receptors. Thus, TSST-1 and perhaps other exotoxins produced by Gram-positive bacteria induce NO synthase and the increased NO formation may contribute to toxic shock syndrome and possibly to changes in the immune responses that accompany infection.
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Selected References
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- Albina J. E., Abate J. A., Henry W. L., Jr Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation. Role of IFN-gamma in the induction of the nitric oxide-synthesizing pathway. J Immunol. 1991 Jul 1;147(1):144–148. [PubMed] [Google Scholar]
- Bergdoll M. S., Crass B. A., Reiser R. F., Robbins R. N., Davis J. P. A new staphylococcal enterotoxin, enterotoxin F, associated with toxic-shock-syndrome Staphylococcus aureus isolates. Lancet. 1981 May 9;1(8228):1017–1021. doi: 10.1016/s0140-6736(81)92186-3. [DOI] [PubMed] [Google Scholar]
- Billiar T. R., Curran R. D., Stuehr D. J., Stadler J., Simmons R. L., Murray S. A. Inducible cytosolic enzyme activity for the production of nitrogen oxides from L-arginine in hepatocytes. Biochem Biophys Res Commun. 1990 May 16;168(3):1034–1040. doi: 10.1016/0006-291x(90)91133-d. [DOI] [PubMed] [Google Scholar]
- Bohach G. A., Fast D. J., Nelson R. D., Schlievert P. M. Staphylococcal and streptococcal pyrogenic toxins involved in toxic shock syndrome and related illnesses. Crit Rev Microbiol. 1990;17(4):251–272. doi: 10.3109/10408419009105728. [DOI] [PubMed] [Google Scholar]
- Bredt D. S., Snyder S. H. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A. 1990 Jan;87(2):682–685. doi: 10.1073/pnas.87.2.682. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Busse R., Mülsch A. Induction of nitric oxide synthase by cytokines in vascular smooth muscle cells. FEBS Lett. 1990 Nov 26;275(1-2):87–90. doi: 10.1016/0014-5793(90)81445-t. [DOI] [PubMed] [Google Scholar]
- Curran R. D., Ferrari F. K., Kispert P. H., Stadler J., Stuehr D. J., Simmons R. L., Billiar T. R. Nitric oxide and nitric oxide-generating compounds inhibit hepatocyte protein synthesis. FASEB J. 1991 Apr;5(7):2085–2092. doi: 10.1096/fasebj.5.7.1707021. [DOI] [PubMed] [Google Scholar]
- Dembińska-Kieć A., Zmuda A., Marcinkiewicz J., Sinzinger H., Gryglewski R. J. Influence of no-donor (SIN-1) on functions of inflammatory cells. Agents Actions. 1991 Jan;32(1-2):37–40. doi: 10.1007/BF01983305. [DOI] [PubMed] [Google Scholar]
- Doyle M. P., Hoekstra J. W. Oxidation of nitrogen oxides by bound dioxygen in hemoproteins. J Inorg Biochem. 1981 Jul;14(4):351–358. doi: 10.1016/s0162-0134(00)80291-3. [DOI] [PubMed] [Google Scholar]
- Fisher C. J., Jr, Horowitz Z., Albertson T. E. Cardiorespiratory failure in toxic shock syndrome: effect of dobutamine. Crit Care Med. 1985 Mar;13(3):160–165. doi: 10.1097/00003246-198503000-00004. [DOI] [PubMed] [Google Scholar]
- Fleming I., Gray G. A., Julou-Schaeffer G., Parratt J. R., Stoclet J. C. Incubation with endotoxin activates the L-arginine pathway in vascular tissue. Biochem Biophys Res Commun. 1990 Sep 14;171(2):562–568. doi: 10.1016/0006-291x(90)91183-s. [DOI] [PubMed] [Google Scholar]
- Fu J. Y., Masferrer J. L., Seibert K., Raz A., Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem. 1990 Oct 5;265(28):16737–16740. [PubMed] [Google Scholar]
- Förstermann U., Pollock J. S., Schmidt H. H., Heller M., Murad F. Calmodulin-dependent endothelium-derived relaxing factor/nitric oxide synthase activity is present in the particulate and cytosolic fractions of bovine aortic endothelial cells. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1788–1792. doi: 10.1073/pnas.88.5.1788. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gray G. A., Schott C., Julou-Schaeffer G., Fleming I., Parratt J. R., Stoclet J. C. The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats. Br J Pharmacol. 1991 May;103(1):1218–1224. doi: 10.1111/j.1476-5381.1991.tb12327.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gryglewski R. J., Korbut R., Kalecinska A., Zembowicz A. Interaction between stimulators of adenylate and guanylate cyclases in human leukocytes, platelets and arteries. Int J Tissue React. 1989;11(6):269–275. [PubMed] [Google Scholar]
- Gryglewski R. J., Palmer R. M., Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986 Apr 3;320(6061):454–456. doi: 10.1038/320454a0. [DOI] [PubMed] [Google Scholar]
- Herman A., Kappler J. W., Marrack P., Pullen A. M. Superantigens: mechanism of T-cell stimulation and role in immune responses. Annu Rev Immunol. 1991;9:745–772. doi: 10.1146/annurev.iy.09.040191.003525. [DOI] [PubMed] [Google Scholar]
- Hibbs J. B., Jr, Taintor R. R., Vavrin Z. Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987 Jan 23;235(4787):473–476. doi: 10.1126/science.2432665. [DOI] [PubMed] [Google Scholar]
- Hibbs J. B., Jr, Taintor R. R., Vavrin Z., Rachlin E. M. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1988 Nov 30;157(1):87–94. doi: 10.1016/s0006-291x(88)80015-9. [DOI] [PubMed] [Google Scholar]
- Hirose A., Ikejima T., Gill D. M. Established macrophagelike cell lines synthesize interleukin-1 in response to toxic shock syndrome toxin. Infect Immun. 1985 Dec;50(3):765–770. doi: 10.1128/iai.50.3.765-770.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoffman R. A., Langrehr J. M., Billiar T. R., Curran R. D., Simmons R. L. Alloantigen-induced activation of rat splenocytes is regulated by the oxidative metabolism of L-arginine. J Immunol. 1990 Oct 1;145(7):2220–2226. [PubMed] [Google Scholar]
- Igarashi H., Fujikawa H., Usami H. Effects of drugs on the pyrogenicity of toxic shock syndrome toxin 1 and its capacity to enhance susceptibility to the lethal effects of endotoxic shock in rabbits. Rev Infect Dis. 1989 Jan-Feb;11 (Suppl 1):S210–S213. doi: 10.1093/clinids/11.supplement_1.s210. [DOI] [PubMed] [Google Scholar]
- Ignarro L. J. Heme-dependent activation of soluble guanylate cyclase by nitric oxide: regulation of enzyme activity by porphyrins and metalloporphyrins. Semin Hematol. 1989 Jan;26(1):63–76. [PubMed] [Google Scholar]
- Ikejima T., Dinarello C. A., Gill D. M., Wolff S. M. Induction of human interleukin-1 by a product of Staphylococcus aureus associated with toxic shock syndrome. J Clin Invest. 1984 May;73(5):1312–1320. doi: 10.1172/JCI111334. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ikejima T., Okusawa S., van der Meer J. W., Dinarello C. A. Induction by toxic-shock-syndrome toxin-1 of a circulating tumor necrosis factor-like substance in rabbits and of immunoreactive tumor necrosis factor and interleukin-1 from human mononuclear cells. J Infect Dis. 1988 Nov;158(5):1017–1025. doi: 10.1093/infdis/158.5.1017. [DOI] [PubMed] [Google Scholar]
- Jupin C., Anderson S., Damais C., Alouf J. E., Parant M. Toxic shock syndrome toxin 1 as an inducer of human tumor necrosis factors and gamma interferon. J Exp Med. 1988 Mar 1;167(3):752–761. doi: 10.1084/jem.167.3.752. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Knowles R. G., Merrett M., Salter M., Moncada S. Differential induction of brain, lung and liver nitric oxide synthase by endotoxin in the rat. Biochem J. 1990 Sep 15;270(3):833–836. doi: 10.1042/bj2700833. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kwon N. S., Nathan C. F., Gilker C., Griffith O. W., Matthews D. E., Stuehr D. J. L-citrulline production from L-arginine by macrophage nitric oxide synthase. The ureido oxygen derives from dioxygen. J Biol Chem. 1990 Aug 15;265(23):13442–13445. [PubMed] [Google Scholar]
- Lepoivre M., Chenais B., Yapo A., Lemaire G., Thelander L., Tenu J. P. Alterations of ribonucleotide reductase activity following induction of the nitrite-generating pathway in adenocarcinoma cells. J Biol Chem. 1990 Aug 25;265(24):14143–14149. [PubMed] [Google Scholar]
- Lin Y. S., Patel M. R., Linna T. J., Rogers T. J. Suppression of cytolytic T-cell activity by staphylococcal enterotoxin B-induced suppressor cells: role of interleukin 2. Cell Immunol. 1986 Nov;103(1):147–159. doi: 10.1016/0008-8749(86)90076-6. [DOI] [PubMed] [Google Scholar]
- Marletta M. A., Yoon P. S., Iyengar R., Leaf C. D., Wishnok J. S. Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate. Biochemistry. 1988 Nov 29;27(24):8706–8711. doi: 10.1021/bi00424a003. [DOI] [PubMed] [Google Scholar]
- McCall T. B., Feelisch M., Palmer R. M., Moncada S. Identification of N-iminoethyl-L-ornithine as an irreversible inhibitor of nitric oxide synthase in phagocytic cells. Br J Pharmacol. 1991 Jan;102(1):234–238. doi: 10.1111/j.1476-5381.1991.tb12159.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Micusan V. V., Desrosiers M., Gosselin J., Mercier G., Oth D., Bhatti A. R., Heremans H., Billiau A. Stimulation of T cells and induction of interferon by toxic shock syndrome toxin 1. Rev Infect Dis. 1989 Jan-Feb;11 (Suppl 1):S305–S312. doi: 10.1093/clinids/11.supplement_1.s305. [DOI] [PubMed] [Google Scholar]
- Mills C. D. Molecular basis of "suppressor" macrophages. Arginine metabolism via the nitric oxide synthetase pathway. J Immunol. 1991 Apr 15;146(8):2719–2723. [PubMed] [Google Scholar]
- Moncada S., Palmer R. M. Inhibition of the induction of nitric oxide synthase by glucocorticoids: yet another explanation for their anti-inflammatory effects? Trends Pharmacol Sci. 1991 Apr;12(4):130–131. doi: 10.1016/0165-6147(91)90528-z. [DOI] [PubMed] [Google Scholar]
- Mulligan M. S., Hevel J. M., Marletta M. A., Ward P. A. Tissue injury caused by deposition of immune complexes is L-arginine dependent. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6338–6342. doi: 10.1073/pnas.88.14.6338. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Musser J. M., Hauser A. R., Kim M. H., Schlievert P. M., Nelson K., Selander R. K. Streptococcus pyogenes causing toxic-shock-like syndrome and other invasive diseases: clonal diversity and pyrogenic exotoxin expression. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2668–2672. doi: 10.1073/pnas.88.7.2668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakano T., Ohara O., Teraoka H., Arita H. Glucocorticoids suppress group II phospholipase A2 production by blocking mRNA synthesis and post-transcriptional expression. J Biol Chem. 1990 Jul 25;265(21):12745–12748. [PubMed] [Google Scholar]
- Nathan C. F., Hibbs J. B., Jr Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol. 1991 Feb;3(1):65–70. doi: 10.1016/0952-7915(91)90079-g. [DOI] [PubMed] [Google Scholar]
- Olken N. M., Rusche K. M., Richards M. K., Marletta M. A. Inactivation of macrophage nitric oxide synthase activity by NG-methyl-L-arginine. Biochem Biophys Res Commun. 1991 Jun 14;177(2):828–833. doi: 10.1016/0006-291x(91)91864-9. [DOI] [PubMed] [Google Scholar]
- Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
- Parker M. M., Parrillo J. E. Septic shock. Hemodynamics and pathogenesis. JAMA. 1983 Dec 23;250(24):3324–3327. [PubMed] [Google Scholar]
- Parsonnet J., Gillis Z. A. Production of tumor necrosis factor by human monocytes in response to toxic-shock-syndrome toxin-1. J Infect Dis. 1988 Nov;158(5):1026–1033. doi: 10.1093/infdis/158.5.1026. [DOI] [PubMed] [Google Scholar]
- Parsonnet J., Gillis Z. A., Richter A. G., Pier G. B. A rabbit model of toxic shock syndrome that uses a constant, subcutaneous infusion of toxic shock syndrome toxin 1. Infect Immun. 1987 May;55(5):1070–1076. doi: 10.1128/iai.55.5.1070-1076.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Poindexter N. J., Schlievert P. M. Suppression of immunoglobulin-secreting cells from human peripheral blood by toxic-shock-syndrome toxin-1. J Infect Dis. 1986 Apr;153(4):772–779. doi: 10.1093/infdis/153.4.772. [DOI] [PubMed] [Google Scholar]
- Radomski M. W., Palmer R. M., Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci U S A. 1990 Dec;87(24):10043–10047. doi: 10.1073/pnas.87.24.10043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reeves M. W., Arko R. J., Chandler F. W., Bridges N. B. Affinity purification of staphylococcal toxic shock syndrome toxin 1 and its pathologic effects in rabbits. Infect Immun. 1986 Feb;51(2):431–439. doi: 10.1128/iai.51.2.431-439.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schlievert P. M. Enhancement of host susceptibility to lethal endotoxin shock by staphylococcal pyrogenic exotoxin type C. Infect Immun. 1982 Apr;36(1):123–128. doi: 10.1128/iai.36.1.123-128.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schlievert P. M., Shands K. N., Dan B. B., Schmid G. P., Nishimura R. D. Identification and characterization of an exotoxin from Staphylococcus aureus associated with toxic-shock syndrome. J Infect Dis. 1981 Apr;143(4):509–516. doi: 10.1093/infdis/143.4.509. [DOI] [PubMed] [Google Scholar]
- Snyder S. H., Bredt D. S. Nitric oxide as a neuronal messenger. Trends Pharmacol Sci. 1991 Apr;12(4):125–128. doi: 10.1016/0165-6147(91)90526-x. [DOI] [PubMed] [Google Scholar]
- Stuehr D. J., Marletta M. A. Synthesis of nitrite and nitrate in murine macrophage cell lines. Cancer Res. 1987 Nov 1;47(21):5590–5594. [PubMed] [Google Scholar]
- Stuehr D. J., Nathan C. F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. doi: 10.1084/jem.169.5.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thiemermann C., Vane J. Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. Eur J Pharmacol. 1990 Jul 17;182(3):591–595. doi: 10.1016/0014-2999(90)90062-b. [DOI] [PubMed] [Google Scholar]
- Todd J. K., Ressman M., Caston S. A., Todd B. H., Wiesenthal A. M. Corticosteroid therapy for patients with toxic shock syndrome. JAMA. 1984 Dec 28;252(24):3399–3402. [PubMed] [Google Scholar]
- Todd J., Fishaut M., Kapral F., Welch T. Toxic-shock syndrome associated with phage-group-I Staphylococci. Lancet. 1978 Nov 25;2(8100):1116–1118. doi: 10.1016/s0140-6736(78)92274-2. [DOI] [PubMed] [Google Scholar]
- Wu K. K., Sanduja R., Tsai A. L., Ferhanoglu B., Loose-Mitchell D. S. Aspirin inhibits interleukin 1-induced prostaglandin H synthase expression in cultured endothelial cells. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2384–2387. doi: 10.1073/pnas.88.6.2384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Azavedo J. C. Animal models for toxic shock syndrome: overview. Rev Infect Dis. 1989 Jan-Feb;11 (Suppl 1):S205–S209. doi: 10.1093/clinids/11.supplement_1.s205. [DOI] [PubMed] [Google Scholar]