Toll-like receptor signaling modulates STAT1 regulated gene expression in macrophages.

摘要

Macrophages play an important role in immune responses by ingesting particulate matter in the body and presenting antigenic peptides on major histocompatability complex (MHC) molecules to T cells. Tap-1 and LMP2 are components on the MHC class I antigen processing pathway. The transcription of both Tap-1 and LMP2 is increased by IFN-γ through the action of the transcription factor STAT1. Toll-like receptors (TLR) are present on macrophages and signal the presence of bacteria and their products. Previously, our lab showed that the bacterial cell wall component LPS, which signals through TLR4, synergized with IFN-γ to increase transcription of Tap-1 through STAT1. This project focused on TLR4 signaling, as well as TLR2 and TLR9. I asked if other TLRs modulate the expression of Tap-1 through STAT1. Studies in THP-1 cells, showed that through TLR2 and TLR 9, petidoglycan and unmethylated CpG DNA also synergized with IFN-γ through STAT1 to increase Tap-1 transcription. Increases in Tap-1 were mediated by TLR-induced p38 activation and increased STAT1 phosphorylation. In contrast, p38 activation by TLR or TNF-α did not translate into an increase in STAT1 phosphorylation or increased Tap-1 transcription in an epithelial cell line. While short term stimulation with IFN-γ and LPS increased STAT1 responses, longer stimulation with both agents decreased STAT1 phosphorylation. Addition of LPS increased the off-rate of nuclear STAT1 tyrosine phosphorylation which correlated with the LPS induced expression of the nuclear phosphatase MKP-1. Thus, TLR signaling may initially boost expression of STAT1 dependent genes, but later provides means for decreasing their expression via MKP-1.