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The Proinflammatory Mediator CD40 Ligand Is Increased in the Metabolic Syndrome and Modulated by Adiponectin

Division of Cardiovascular Sciences (C.N., C.I., J.D., N.V.), Centre for Applied Medical Research, University of Navarra, and Departments of Clinical Chemistry (P.R., N.V.), Internal Medicine (I.C.), and Cardiology and Cardiovascular Surgery (J.D.), University Clinic of Navarra, 31008 Pamplona, Spain

Address all correspondence and requests for reprints to: Nerea Varo, Ph.D., Center for Applied Medical Research, Avda Pío XII 55, 31008 Pamplona, Spain. E-mail: nvaro{at}unav.es.

Objectives: We hypothesized that the CD40/CD40 ligand (CD40L) system is up-regulated in the metabolic syndrome (MS) and modulated by adiponectin (AN). The objectives were: 1) to compare plasma and monocyte CD40L in patients with MS and controls and its association with clinical and biochemical parameters, 2) to investigate platelets as a source of soluble CD40L (sCD40L), and 3) to analyze the effects of AN on CD40/CD40L.

Methods: Plasma sCD40L and AN were measured in 246 controls and 128 patients with MS by ELISA. Monocyte CD40/CD40L expression and platelet CD40L content and release were compared in patients with MS and controls. Monocytes and endothelial cells were cultured with AN and CD40/CD40L expression determined by real-time RT-PCR and Western blotting.

Results: Patients with MS had higher sCD40L and lower AN levels than controls (0.89 ± 0.1 vs. 0.76 ± 0.07 ng/ml and 10.10 ± 0.65 vs. 12.99 ± 0.80 µg/ml, P < 0.05). Monocyte CD40/CD40L expression was higher (P < 0.05) in patients than controls (CD40: 1.31 ± 0.31 vs. 0.80 ± 0.14 arbitrary units; CD40L: 1.24 ± 0.85 vs. 0.43 ± 0.14 pg/µg protein). No differences were observed on CD40L content between resting platelets from patients with MS and controls (7.7 ± 3.5 vs. 7.2 ± 2.2 pg/µg protein). Stimulated platelets from patients with the MS released more (P < 0.05) sCD40L than controls (582 ± 141 vs. 334 ± 60% change vs. nonstimulated platelets). AN reduced CD40L mRNA and protein expression in monocytes from MS patients and endothelial cells.

Conclusions: The enhanced sCD40L and cellular CD40L expression in the MS suggests that CD40L is of pathophysiological relevance in MS. Also, a new antiinflammatory effect of AN is described through the modulation of the CD40/CD40L system.