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Signal integration in lipopolysaccharide (LPS)-stimulated murine macrophages

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA, vogel{at}bob.usuhs.mil

Matthew J. Hirschfeld

Department of Pathology, University of Utah, Salt Lake City, Utah, USA

Pin-Yu Perera

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

Using a panel of LPS-inducible genes, selected for the capacity of their products to contribute to endotoxicity, normal macrophages were compared to macrophages deficient in CD14, CD11b/CD18, or TLR4 to elicit gene expression in response to Escherichia coli LPS or the LPS mimetic, Taxol. All genes were TLR4-dependent. At low doses of LPS or Taxol, all genes were also CD14-dependent; however, IP-10 and ICSBP remained poorly inducible even at much higher concentrations. A distinct subset of genes (COX-2, IL-12 p40, and IL-12 p35) was CD11b/CD18-dependent. NF-B translocation and MAPK phosphorylation were dysregulated in receptor-deficient macrophages. In contrast to E. coli LPS, a Porphyromonas gingivalis LPS preparation was found to be TLR2-, rather than TLR4-dependent, and resulted in differential expression of genes within the panel. These data suggest that: (i) TLR4 is necessary, but not sufficient, to induce the full repertoire of genes examined; (ii) CD14 and CD11b/CD18 facilitate signaling for induction of select subsets of genes that are also TLR4-dependent; and (iii) signaling through TLR2 versus TLR4 differs quantitatively/qualitatively. These data support an LPS signaling complex on murine macrophages that minimally includes CD14, CD11b/CD18, and TLR4 to respond to E. coli LPS to elicit the full spectrum of gene expression.

Journal of Endotoxin Research, Vol. 7, No. 3, 237-241 (2001)
DOI: 10.1177/09680519010070030801


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