CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression

Overproduction of inflammatory mediators by macrophages in response to Gram -negative LPS has been implicated in septic shock. Recent reports indicate that three membrane-associated proteins, CD14, CD11b/CD18, and Toll-like re ceptor (TLR) 4, may serve as LPS recognition and/or signaling receptors in murine macrophages, Therefore, the relative contribution of these proteins in the induction of cyclooxygenase 2 (COX-2), IL-12 p35, IL-12 p40, TNF-alp ha, IFN-inducible protein (IP)-10, and IFN consensus sequence binding prote in (ICSBP) genes in response to LPS or the LPS-mimetic, Taxol, was examined using macrophages derived from mice deficient for these membrane-associate d proteins. The panel of genes selected reflects diverse macrophage effecto r functions that contribute to the pathogenesis of septic shock. Induction of the entire panel of genes in response to low concentrations of LPS or Ta xol requires the participation of both CD14 and TLR4, whereas high concentr ations of LPS or Taxol elicit the expression of a subset of LPS-inducible g enes in the absence of CD14, In contrast, for optimal induction of COX-2, I L-12 p35, and IL-12 p40 genes by low concentrations of LPS or by all concen trations of Taxol, CD11b/CD18 was also required. Mitigated induction of COX -2, IL-12 p35, and IL-12 p40 gene expression by CD11b/CD11-deficient macrop hages correlated with a marked inhibition of NF-kappaB nuclear translocatio n and mitogen-activated protein kinase (MAPK) activation in response to Tax ol and of NF-kappaB nuclear translocation in response to LPS, These finding s suggest that for expression of a full repertoire of LPS-/Taxol-inducible genes, CD14, TLR4, and CD11b/CD18 must be coordinately engaged to deliver o ptimal signaling to the macrophage.