interleukin-8 and 1-(carboxymethylthio)tetradecane

Tetradecylthioacetic acid (TTA) is a bioactive 3-thia fatty acid, giving hypolipidemic response, inhibiting the proliferation and increasing the differentiation of normal adult epidermal keratinocytes and showing anti-oxidant and anti-inflammatory effects. Psoriasis is an inflammatory disease associated with abnormalities in lipid profile, lipid peroxidation, antioxidant capacity, eicosanoid metabolism and increased frequency of cardiovascular events. On this background we have conducted a pilot study to explore the hypothesis that this modified fatty acid could improve dyslipidemia and reduce inflammation in psoriatic patients. In this double-blinded, placebo-controlled study, we assessed the metabolic effects of systemic TTA in a limited number of patients with mild to moderate psoriasis, 1000 mg TTA daily for 28 days. The most important findings were: (i) TTA reduced plasma total cholesterol, non HDL-cholesterol, LDL/HDL cholesterol ratio, triglycerides and total fatty acids; (ii) TTA decreased plasma TNF-α, IL-8 and VCAM-1; and (iii) plasma fatty acid composition changed with an increased level of monounsaturated fatty acids and decreased n-3 polyunsaturated fatty acids. In conclusion TTA exerts both hypolipidemic and anti-inflammatory effects in psoriasis patients. The results further indicate that TTA can be of therapeutic benefit for a subgroup of psoriatic patients.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Double-Blind Method; Female; Humans; Hypolipidemic Agents; Interleukin-8; Lipids; Male; Middle Aged; Pilot Projects; Psoriasis; Sulfides; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Young Adult

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.. 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.. 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.

Topics: Adult; Aged; Animals; Anti-Inflammatory Agents; Antioxidants; Cell Adhesion; Cells, Cultured; Chemokine CCL2; Endothelium, Vascular; Female; Gene Expression; Humans; Interleukin-8; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Middle Aged; Monocytes; Neutrophils; PPAR alpha; PPAR delta; Psoriasis; Sulfides; Tumor Necrosis Factor-alpha; Umbilical Veins; Vascular Cell Adhesion Molecule-1