Specificity from Toll Receptors

Abstract

The Toll-like receptors 2 and 4 (TLR2 and TLR4) function in detection of bacterial infection, responding to lipopolysaccharide (LPS) from Gram-negative bacteria or peptidoglycan (PGN) from Gram-positive bacteria, respectively. Although the two receptors generate similar signaling outputs, evidence is accumulating that responses to the two are notably distinct. In fact, Carl et al. show that even when using the same signaling elements, the TLR2 and TLR4 signals act distinctly to control expression of a single gene target. The authors monitored activation of the gene encoding the secretory interleukin-1 receptor antagonist, sIL-1Ra. Although activation of either TLR2 or TLR4 activated expression of sIL-1Ra mRNA, the two signals acted synergistically. In both cases, promoter deletion analysis showed that the transcription factor PU.1 was required for a full response, and pharmacological inhibition of the p38 stress-activated protein kinase showed that the kinase was also required for full transcriptional activation. Nevertheless, these common elements had distinct roles depending on whether cultured murine macrophages were treated with LPS or PGN. The promoter regions required for the responses to TLR2 or TLR4 were different and even the p38-dependent response mapped to distinct regions of the promoter, with the response to TLR2-activated p38 requiring PU.1, whereas the p38-mediated signal from TLR4 did not. The authors conclude that TLR2 and TL4 must activate different DNA binding proteins (to account for the distinct promoter regions required) and that, even when using very similar pathways (through p38 and PU.1), signals from the two receptors result in distinct gene regulatory responses. V. S. Carl, K. Brown-Steinke, M. J. H. Nicklin, M. F. Smith Jr., Toll-like receptor 2 and 4 (TLR2 and TLR4) agonists differentially regulate secretory interleukin-1 receptor antagonist gene expression in macrophages. J. Biol.Chem. 277 , 17448-17456 (2002). [Abstract] [Full Text]