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 activa...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-09, Vol.278 (39), p.37041-37051
Main Authors: Lee, Joo Y., Ye, Jianping, Gao, Zhanguo, Youn, Hyung S., Lee, Won H., Zhao, Ling, Sizemore, Nywana, Hwang, Daniel H.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Animals
Antigens, Differentiation - physiology
Cell Line
Cyclooxygenase 2
docosahexaenoic acid
Docosahexaenoic Acids - pharmacology
dodecanoic acid
Fatty Acids - pharmacology
gene expression
gene expression regulation
Humans
immune response
inflammation
Interleukin-1 Receptor-Associated Kinases
Isoenzymes - biosynthesis
macrophages
Membrane Glycoproteins - physiology
Membrane Proteins
Mice
Myeloid Differentiation Factor 88
NF-kappa B - metabolism
nuclear factor kappa B
phosphatidylinositol 3-kinase
Phosphatidylinositol 3-Kinases - physiology
Phosphorylation
prostaglandin synthase
Prostaglandin-Endoperoxide Synthases - biosynthesis
Protein Kinases - physiology
protein phosphorylation
Protein-Serine-Threonine Kinases
Proteins - physiology
Proto-Oncogene Proteins - physiology
Proto-Oncogene Proteins c-akt
receptors
Receptors, Cell Surface - physiology
Receptors, Immunologic - physiology
signal transduction
Signal Transduction - physiology
TNF Receptor-Associated Factor 6
Toll-Like Receptor 4
Toll-Like Receptors
transcription factors
transmembrane proteins
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Summary: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 NFκB activation was inhibited by a dominant-negative mutant of TLR4, MyD88, IRAK-1, TRAF6, or IκBα 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 NFκB activation, p65 transactivation, and cyclooxygenase-2 (COX-2) expression induced by lauric acid or constitutively active (CA) TLR4. AKT(DN) blocked MyD88-induced NFκB activation, suggesting that AKT is a MyD88-dependent downstream signaling component of TLR4. AKT(CA) was sufficient to induce NFκB activation and COX-2 expression. These results demonstrate that NFκB 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 NFκB 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.
ISSN:0021-9258
1083-351X
1083-351X
DOI:10.1074/jbc.M305213200