Abstract
Macrophages play a central role in host defense mechanisms. Many of the functions of macrophages are acquired after their exposure to stimuli encountered in the tissue microenvironment. Lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, is a potent macrophage-activating stimulus that induces expression of many genes that are necessary for host defense. Recent studies of LPS-mediated intracellular signaling mechanisms have revealed that the toll-like receptor 4 (TLR4) is the primary signaling receptor for LPS. After ligation with LPS, TLR4 leads to recruitment of adapter molecules and kinases, including MyD88, IRAK, TRAF6, and IKKs, and subsequently activates transcription factor NF-κB, which mediates the transcriptional activation of many inflammatory genes. Although LPS directly activates NF-κB, LPS also acts indirectly through the intermediate production of cytokines, which can alter macrophage gene expression through autocrine/paracrine loops. LPS-induced type I interferon (IFN-alpha and IFN-beta) is essential for IP-10, IRF-1 and iNOS gene expression through the indirect activation of STAT1. Thus, substantial complexity is created by direct and indirect activation of transcription factors in the pattern of LPS-induced gene expression during bacterial infection.
