The expression of MHC class II genes is strictly tissue specific. In a limited number of cells, the expression of these genes is inducible by cytokines and only in dendritic and B cells is expression constitutive. LPS blocks the cytokine-dependent induction of these genes, but enhances their expression in dendritic and the B cell line A20. We have observed that LPS increased surface expression by raising I-A protein and mRNA levels. LPS does not enhance the expression of the transactivator CIITA. In transient transfection experiments, LPS induced the expression of the I-Abeta promoter, which contains an AP-1 box located between 1722 and 1729 bp upstream of the transcriptional start site. Mutation of this box abrogated the effect of LPS. The AP-1 box still responded to LPS when we moved it to -611 bp or even when it was in the opposite direction. LPS induced a complex that bound to the AP-1 box. However, in dendritic cells, the complex comprised c-jun and c-fos while in A20 cells only c-jun. This was confirmed by chromatin immune precipitation assays and the distinct induction of c-jun and c-fos mRNAs. Therefore, our results indicate that LPS exerts a novel regulatory mechanism in the control of MHC class II gene expression.