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 presen tation and the vigor of CD4(+) T cell immunity, We show that LPS may e ither inhibit or augment IfN-gamma-induced MHC class II on macrophages depending on the sequence of the IFN-gamma and LPS signals, LPS inhib ited MHG class II when added simultaneously with IFN-gamma, but augmen ted class II expression when added after IFN-gamma, Inhibition was due to nitric oxide (NO), which was only produced if LPS was given simult aneously with IFN-gamma, However, even when NO production was inhibite d, LPS given simultaneously with IFN-gamma did not augment MHC class I I expression, This suggests that LPS delivers different signals when g iven simultaneously vs after IFN-gamma. LPS augmentation of class II e xpression was functionally important because it correlated with increa sed 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 express ion if NO was produced, but augmented it in the absence of NO formatio n, Studies with a neutralizing anti-TNF-alpha Ab, however, indicate th at LPS augmentation of MHC class II did not require TNF-alpha, LPS aug mentation involved a different mechanism than IFN-gamma induction of M HC class II. LPS augmentation occurred at a post-transcriptional level , whereas IFN-gamma-induction occurred at the level of gene transcript ion, LPS augmentation was apparent after 2 h of stimulation by LPS, wh ile IFN-gamma induction of class II expression required more than 8 h.