Antiinflammatory effects of tetradecylthioacetic acid involve both peroxisome proliferator-activated receptor alpha-dependent and -independent pathways.
OBJECTIVE
Tetradecylthioacetic acid (TTA) is a hypolipidemic antioxidant with immunomodulating properties involving activation of peroxisome proliferator-activated receptors (PPARs). Human endothelial cells express PPARs. We hypothesized that TTA could modulate endothelial cell activation at least partly through PPAR-related mechanisms.


RESULTS
We explored this hypothesis by different experimental approaches involving both in vitro studies in human endothelial cells (HUVECs) and in vivo studies in humans and PPAR-alpha-/- mice. Our main findings were as follows: (1) TTA suppressed the tumor necrosis factor alpha-induced expression of vascular cell adhesion molecule 1 (VCAM-1) and interleukin 8 (IL-8) in HUVECs. (2) No TTA-mediated attenuation of VCAM-1 and chemokine expression was seen in the liver of PPAR-alpha-/- mice. (3) Whereas TTA markedly enhanced PPAR-alpha-target genes in the liver of wild-type, but not of PPAR-alpha-/-, mice, no such effect on PPAR-alpha-target genes was seen in HUVECs. (4) The relevance of our findings to human disease was suggested by a TTA-mediated downregulation of serum levels of soluble VCAM-1 and IL-8 in psoriasis patients.


CONCLUSIONS
We show that TTA has the ability to attenuate tumor necrosis factor alpha-mediated endothelial cell activation, further supporting antiinflammatory effects of this fatty acid, possibly involving both PPAR-alpha-dependent and -independent pathways.
Dyrøy
Endre
E
Institute of Medicine, Section of Medical Biochemistry, University of Bergen, Haukeland University Hospital, Bergen, Norway. endre.dyroy@med.uib.no
Yndestad
Arne
A
Ueland
Thor
T
Halvorsen
Bente
B
Damås
Jan Kristian
JK
Aukrust
Pål
P
Berge
Rolf K
RK
D000328:Adult; D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000097:blood / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology; D009504:Neutrophils / Q000166:cytology; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood / Q000235:genetics
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016209:Interleukin-8; D047493:PPAR alpha; D047494:PPAR delta; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C062078:1-(carboxymethylthio)tetradecane