Regulation of adhesion molecule expression in human endothelial and smooth muscle cells by omega-3 fatty acids and conjugated linoleic acids: involvement of the transcription factor NF-kappaB?

M Goua, S Mulgrew, J Frank, D Rees, A A Sneddon, K W J Wahle
Prostaglandins, Leukotrienes, and Essential Fatty Acids 2008, 78 (1): 33-43
We previously showed conjugated linoleic acids (CLA) inhibited TNF-alpha-induced monocyte (THP-1) adhesion to human umbilical vein endothelial cells (HUVEC) in vitro which involved an increase in platelet activating factor (PAF). Here we show adhesion molecule (ADM) regulation by fatty acids and the differing role of nuclear factor kappa B (NF-kappaB) activation in HUVEC and vascular smooth muscle cells (vSMC). CLA and omega-3 long-chain polyunsaturated fatty acids (PUFA) (FA) reduced TNF-alpha-induced expression of ADMs (intercellular adhesion molecule-1 (ICAM-1); vascular cell adhesion molecule-1 (VCAM-1) but not E-selectin) on HUVEC and vSMC to different extents depending on FA type and concentration, cell type and method of analysis. IkappaBalpha phosphorylation in HUVEC and vSMC and transient transfection with NF-kappaB-luciferase reporter plasmid (HUVEC only) indicated differential NF-kappaB involvement during FA modulation (cis-9, trans-11; trans-10, cis-12 and a 50:50 mix of both CLA isomers; eicosapentaenoic acid (EPA); docosahexaenoic acid (DHA)). TNF-alpha-induced ADM expression in both cell types by 2-10-fold. In HUVEC, CLA t10, c12 and CLA mix (50:50 mixture of CLA c9, t11 and t10, c12) and EPA and DHA reduced ICAM-1 expression (15-35%) at 12.5, 25 and/or 50 microM. VCAM-1 expression was reduced by 25 microM t10, c12 isomer and mix; omega-3 PUFA and other concentrations of CLA and TNF-alpha-induced E-selectin expression were unaffected. TNFalpha-induced inhibitor kappa B (IkappaB) phosphorylation was biphasic peaking at 5 min in both cell types and 60 and 120 min in HUVEC and SMC, respectively. IkappaBalpha phosphorylation and NF-kappaB activity was reduced (29% and 30%, respectively) by 25 microM CLA mix. n-3 PUFA did not reduce IkappaBalpha phosphorylation or NF-kappaB activity but reduced ADM expression. We show that n-3 PUFA and CLA reduce expression of ADM on HUVEC and vSMC. This reflected reduced adherence of monocytes to HUVEC previously reported by our group. Reduction of ICAM-1 and VCAM-1 protein expression by n-3 PUFA was less dependent on the NF-kappaB pathway than reduction by CLA which reflected the parallel attenuation of NF-kappaB activity. This indicated involvement of other transcription factors (i.e. AP-1) in the FA regulation of ADM expression and has, to our knowledge, not been previously reported.

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