Bacterial superantigen-induced human lymphocyte responses are nitric oxide dependent and mediated by IL-12 and IFN-gamma.
Bacterial superantigens cause marked proliferation of T cells and release of lymphokines. Nitric oxide, derived from the conversion of L-arginine to L-citrulline, inhibits this activation in murine cells. We have now investigated the roles of IL-12, IFN-gamma, lymphotoxin-alpha, and nitric oxide during superantigen-induced human lymphocyte activation. Lymphocyte activation was determined by measurement of proliferative responses and lymphokine release. Both toxic shock syndrome toxin-1 from Staphylococcus aureus and recombinant streptococcal pyrogenic exotoxin A induced proliferation and production of IFN-gamma, lymphotoxin-alpha, and IL-12 by human mononuclear cells in a time-dependent fashion. The release of IFN-gamma was abrogated by a neutralizing Ab to IL-12, but lymphocyte proliferative responses were unaffected. A neutralizing Ab to IFN-gamma prevented the release of lymphotoxin-alpha, but did not affect proliferation. The neutralization of lymphotoxin-alpha using two different Abs did not affect IFN-gamma release or proliferation. In contrast to previous findings in mice, the arginine analogue, NG-monomethyl-L-arginine, significantly inhibited both proliferation and lymphokine release by superantigen-stimulated human cells. Thus, the release of lymphotoxin-alpha by lymphocytes following superantigen stimulation is dependent upon the presence of IFN-gamma; the IFN-gamma response is in turn under the control of IL-12. There is no evidence that nitric oxide plays an inhibitory role during superantigen-mediated human lymphocyte activation. Indeed, arginine is a prerequisite for such activation.
Sriskandan
S
S
Department of Infectious Diseases and Bacteriology, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
Evans
T J
TJ
Cohen
J
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001426:Bacterial Proteins; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005098:Exotoxins / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D018089:Superantigens / Q000008:administration & dosage* / Q000235:genetics; D019323:omega-N-Methylarginine
D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D005098:Exotoxins; D008233:Lymphotoxin-alpha; D008565:Membrane Proteins; D009573:Nitrites; C117980:SpeA protein, Streptococcus pyogenes; D018089:Superantigens; C027951:erythrogenic toxin; D018664:Interleukin-12; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine; D019001:Nitric Oxide Synthase