Saturated Fatty Acids, but Not Unsaturated Fatty Acids, Induce the Expression of Cyclooxygenase-2 Mediated through Toll-like Receptor 4*

By J. Y. Lee, K. Sohn, S. Rhee, D. Hwang. Journal of Biological Chemistry, 2001

1,277 citations recorded by the source corpus.

Results from our previous studies demonstrated that activation of Toll-like receptor 4 (Tlr4), the lipopolysaccharide (LPS) receptor, is sufficient to induce nuclear factor κB activation and expression of inducible cyclooxygenase (COX-2) in macrophages. Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are essential for biological activities of LPS. Thus, we determined whether these fatty acids modulate LPS-induced signaling pathways and COX-2 expression in monocyte/macrophage cells (RAW 264.7). Results show that SFAs, but not unsaturated fatty acids (UFAs), induce nuclear factor κB activation and expression of COX-2 and other inflammatory markers. This induction is inhibited by a dominant-negative Tlr4. UFAs inhibit COX-2 expression induced by SFAs, constitutively active Tlr4, or LPS. However, UFAs fail to inhibit COX-2 expression induced by activation of signaling components downstream of Tlr4. Together, these results suggest that both SFA-induced COX-2 expression and its inhibition by UFAs are mediated through a common signaling pathway derived from Tlr4. These results represent a novel mechanism by which fatty acids modulate signaling pathways and target gene expression. Furthermore, these results suggest a possibility that propensity of monocyte/macrophage activation is modulated through Tlr4 by different types of free fatty acids, which in turn can be altered by kinds of dietary fat consumed.

Subfields: Immunology, Nutrition and Dietetics, Pharmacology

View Paper: https://www.semanticscholar.org/paper/bc59089d6181c0895686ce0c32e98499bd067fc4

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In Immunology

1. M. Wymann
2. S. Shoelson
3. H. Kwon
4. J. Pessin
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6. M. Donath

Citations in the corpus

• INFLAMMATION AND LIPID SIGNALING IN THE ETIOLOGY OF INSULIN RESISTANCE (2012, neutral): “A precedent for this type of mechanism is provided by the ability of CD36, a fatty acid transporter and oxidzed low-density lipoprotein (LDL) receptor, to interact with Tlr2 and induce signaling in response to oxidized LDL (Seimon et al., 2010; Stewart et al., 2010).”
• Insulin receptor signaling in normal and insulin-resistant states. (2014, background): “Interestingly, saturated FA can also activate this pathway (Lee et al. 2001; Shi et al. 2006), indicating a potential role for these receptors in obesity-driven inflammation.”
• Type 2 diabetes as an inflammatory disease (2011, background): “FFAs may stimulate the production pro-inflammatory molecules by direct activation of TLR2 and TLR4, which can sense lipids, or indirectly through FFA metabolites such as ceramid”