Augmentation or inhibition of IFN-γ-induced MHC class II expression by lipopolysaccharides: The roles of TNF-α 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-γ-induced MHC class II on macrophages depending on the sequence of the IFN-γ and LPS signals. LPS inhibited MHC class II when added simultaneously with IFN-γ, but augmented class II expression when added after IFN-γ. Inhibition was due to nitric oxide (NO), which was only produced if LPS was given simultaneously with IFN-γ. However, even when NO production was inhibited, LPS given simultaneously with IFN-γ did not augment MHC class II expression. This suggests that LPS delivers different signals when given simultaneously vs after IFN-γ. LPS augmentation of class II expression was functionally important because it correlated with increased Ag presentation. Augmentation by LPS of IFN-γ-induced class II expression by macrophages has not been previously reported. We found that TNF-α, like LPS, inhibited IFN-γ-induced class II expression if NO was produced, but augmented it in the absence of NO formation. Studies with a neutralizing anti-TNF-α Ab, however, indicate that LPS augmentation of MHC class II did not require TNF-α. LPS augmentation involved a different mechanism than IFN-γ induction of MHC class II. LPS augmentation occurred at a post-transcriptional level, whereas IFN-γ-induction occurred at the level of gene transcription. LPS augmentation was apparent after 2 h of stimulation by LPS, while IFN-γ induction of class II expression required more than 8 h.