Augmentation or inhibition of IFN-gamma-induced MHC class II expression by lipopolysaccharides. The roles of TNF-alpha and nitric oxide, and the importance of the sequence of signaling.
MHC class II expression on macrophages is one determinant of Ag presentation and the vigor of CD4+ T cell immunity. We show that LPS may either inhibit or augment IFN-gamma-induced MHC class II on macrophages depending on the sequence of the IFN-gamma and LPS signals. LPS inhibited MHC class II when added simultaneously with IFN-gamma, but augmented class II expression when added after IFN-gamma. Inhibition was due to nitric oxide (NO), which was only produced if LPS was given simultaneously with IFN-gamma. However, even when NO production was inhibited, LPS given simultaneously with IFN-gamma did not augment MHC class II expression. This suggests that LPS delivers different signals when given simultaneously vs after IFN-gamma. LPS augmentation of class II expression was functionally important because it correlated with increased Ag presentation. Augmentation by LPS of IFN-gamma-induced class II expression by macrophages has not been previously reported. We found that TNF-alpha, like LPS, inhibited IFN-gamma-induced class II expression if NO was produced, but augmented it in the absence of NO formation. Studies with a neutralizing anti-TNF-alpha Ab, however, indicate that LPS augmentation of MHC class II did not require TNF-alpha. LPS augmentation involved a different mechanism than IFN-gamma induction of MHC class II. LPS augmentation occurred at a post-transcriptional level, whereas IFN-gamma-induction occurred at the level of gene transcription. LPS augmentation was apparent after 2 h of stimulation by LPS, while IFN-gamma induction of class II expression required more than 8 h.
D000818:Animals; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000032:analysis*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000502:physiology; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma