Immunosuppression induced by nitric oxide and its inhibition by interleukin-4.
Mice immunized with attenuated Salmonella typhimurium, strain SL3235, while protected against virulent challenge, are unable to mount in vivo and in vitro antibody responses to non-Salmonella antigens, such as tetanus toxoid and sheep red blood cells, and exhibit profoundly suppressed responses to B and T cell mitogens. Suppression of antibody responses is mediated by macrophage (M phi)-released soluble factors, and is completely reversed by treatment with interleukin (IL)-4. The present report identifies the suppressor factor as nitric oxide (NO), and provides evidence for a mechanism by which IL-4 abrogates suppression. Suppressed antibody responses correlated with high levels of NO secretion by splenocytes of SL3235-immunized mice. NO production was observed only in cultures consisting of the adherent cell fraction of immune splenocytes. Further, immunosuppression was reversed by NG-monomethyl-L-arginine (NMLA), a competitive inhibitor of NO synthesis, and was completely blocked by the addition of excess L-arginine. Treatment with IL-4, or anti-interferon (IFN)-gamma monoclonal antibody (mAb), also abrogated suppression. Optimal reversal of suppression was observed only when NMLA, IL-4, or anti-IFN-gamma mAb, was added at day 0 of the 5-day plaque-forming cell assay. Treatment with either IL-4 or anti-IFN-gamma mAb also lead to a sharp inhibition of NO production by immune spleen cells. Moreover, the addition of IL-4 to splenic adherent M phi inhibited their ability to generate NO. Our data characterize an immunoregulatory pathway, involving IFN-gamma and NO, by which M phi mediate immunosuppression and identify IL-4 as a potent inhibitor of this pathway.
al-Ramadi
B K
BK
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140.
Meissler
J J
JJ
Huang
D
D
Eisenstein
T K
TK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects*; D007114:Immunization; D007371:Interferon-gamma / Q000502:physiology; D015847:Interleukin-4 / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000276:immunology; D013154:Spleen / Q000378:metabolism; D019323:omega-N-Methylarginine
D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D015847:Interleukin-4; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine