Conjugated linoleic acid suppresses IRF3 activation via modulation of CD14.
Polyunsaturated fatty acids (PUFA) can modulate the immune response, however the mechanism by which they exert this effect remains unclear. Previous studies have clearly demonstrated that the cis-9, trans-11 isomer of conjugated linoleic acid (c9,t11-CLA), found predominantly in beef and dairy products, can modulate the response of immune cells to the toll-like receptor (TLR) 4 ligand, lipopolysaccharide (LPS). This study aimed to investigate further the mechanism by which these effects are mediated. Treatment of macrophages with c9,t11-CLA significantly decreased CD14 expression and partially blocked its association with lipid rafts following stimulation with LPS. Furthermore the c9,t11-CLA isomer inhibited both nuclear factor-κB (NF-κB) and IRF3 activation following TLR4 ligation while eicosapentaenoic acid (EPA) only suppressed NF-κB activation. Given that the ability of LPS to activate IRF3 downstream of TLR4 depends on internalisation of the TLR4 complex and involves CD14, we examined TLR4 endocytosis. Indeed the internalisation of TLR4 to early endosomes following activation with LPS was markedly inhibited in c9,t11-CLA treated cells. These effects were not seen with the n-3 fatty acid, EPA, which was used as a comparison. Our data demonstrates that c9,t11-CLA inhibits IRF3 activation via its effects on CD14 expression and localisation. This results in a decrease in the endocytosis of TLR4 which is necessary for IRF3 activation, revealing a novel mechanism by which this PUFA exerts its anti-inflammatory effects.
Immunomodulation Group, School of Biotechnology, Dublin City University, Dublin 9, Ireland.
Jennifer K
JK
Dowling
Claire E
CE
McCoy
Sarah L
SL
Doyle
Nadia
N
BenLarbi
Mary
M
Canavan
Luke A
LA
O'Neill
Christine E
CE
Loscher
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D015525:Fatty Acids, Omega-3; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D044243:Linoleic Acids, Conjugated; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014157:Transcription Factors