Submitted to: Journal of Biological Chemistry
Publication Type: Peer reviewed journal
Publication Acceptance Date: 7/1/2003
Publication Date: 7/15/2003
Citation: Lee, J., Ye, J., Gao, Z., Youn, H., Lee, W., Zhao, L., Sizemore, N., Hwang, D.H. 2003. RECIPROCAL MODULATION OF TOLL-LIKE RECEPTOR-4 SIGNALING PATHWAYS INVOLVING MYD88 AND PHOSPHATIDYLINOSITOL 3-KINASE/AKT BY SATURATED AND POLYUNSATURATED FATTY ACIDS. Journal of Biological Chemistry 278 (39) 37041-37051, 2003. Interpretive Summary: Toll-like receptors (TLRs) play a critical role in inducing innate immune responses in mammals by recognizing conserved athogen-associated molecular patterns (PAMPs) of bacteria. So far, ten human TLRs have been cloned. The TLR agonists include lipopolysaccaride (LPS) for TLR4, peptidoglycan for TLR2 and 6, double-stranded RNA for TLR3, flagellin for TLR5, and imidazoquinolines and unmethylated CpG motifs in bacterial DNA for TLR7 and 9, respectively. TLR4 can be activated by non-bacterial agonists such as heat shock protein 60, fibronectin, taxol, respiratory syncytical virus coat protein and saturated fatty acids.
Technical Abstract: Toll-like receptor 4 (TLR4) can be activated by non-bacterial agonists including saturated fatty acids. However, downstream signaling pathways activated by non-bacterial agonists are not known. Thus, we determined the downstream signaling pathways derived from saturated fatty acid-induced TLR4 activation. The results suggest that saturated and polyunsaturated fatty acids reciprocaly modulate the activation of TLR4 and its downstream signaling pathways involving MyD88/IRAK/TRAF6 and P13K/AKT, and further suggest a possibility that TLR4-mediated target gene expression and cellular responses are also differentially modulated by saturated and unsaturated fatty acids.