Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids.
Toll-like receptor-4 (TLR4) can be activated by nonbacterial agonists, including saturated fatty acids. However, downstream signaling pathways activated by nonbacterial agonists are not known. Thus, we determined the downstream signaling pathways derived from saturated fatty acid-induced TLR4 activation. Saturated fatty acid (lauric acid)-induced NFkappaB activation was inhibited by a dominant-negative mutant of TLR4, MyD88, IRAK-1, TRAF6, or IkappaBalpha in macrophages (RAW264.7) and 293T cells transfected with TLR4 and MD2. Lauric acid induced the transient phosphorylation of AKT. LY294002, dominant-negative (DN) phosphatidylinositol 3-kinase (PI3K), or AKT(DN) inhibited NFkappaB activation, p65 transactivation, and cyclooxygenase-2 (COX-2) expression induced by lauric acid or constitutively active (CA) TLR4. AKT(DN) blocked MyD88-induced NFkappaB activation, suggesting that AKT is a MyD88-dependent downstream signaling component of TLR4. AKT(CA) was sufficient to induce NFkappaB activation and COX-2 expression. These results demonstrate that NFkappaB activation and COX-2 expression induced by lauric acid are at least partly mediated through the TLR4/PI3K/AKT signaling pathway. In contrast, docosahexaenoic acid (DHA) inhibited the phosphorylation of AKT induced by lipopolysaccharide or lauric acid. DHA also suppressed NFkappaB activation induced by TLR4(CA), but not MyD88(CA) or AKT(CA), suggesting that the molecular targets of DHA are signaling components upstream of MyD88 and AKT. Together, these results suggest that saturated and polyunsaturated fatty acids reciprocally modulate the activation of TLR4 and its downstream signaling pathways involving MyD88/IRAK/TRAF6 and PI3K/AKT and further suggest the possibility that TLR4-mediated target gene expression and cellular responses are also differentially modulated by saturated and unsaturated fatty acids.
Lee
Joo Y
JY
Western Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Davis, California 95616, USA.
Ye
Jianping
J
Gao
Zhanguo
Z
Youn
Hyung S
HS
Lee
Won H
WH
Zhao
Ling
L
Sizemore
Nywana
N
Hwang
Daniel H
DH
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D002460:Cell Line; D051546:Cyclooxygenase 2; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases; D007527:Isoenzymes / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D051546:Cyclooxygenase 2; D004281:Docosahexaenoic Acids; D005227:Fatty Acids; D053592:Interleukin-1 Receptor-Associated Kinases; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011451:Prostaglandin-Endoperoxide Synthases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C495345:TLR4 protein, human; C496540:PTGS2 protein, human; C494918:AKT1 protein, human