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Pioglitazone Inhibits Toll-Like Receptor Expression and Activity in Human Monocytes and db/db Mice

Laboratory for Atherosclerosis and Metabolic Research (M.R.D., S.P., S.D., I.J.), University of California, Davis Medical Center, Sacramento California 95817; and Veterans Affairs Medical Center (I.J.), Sacramento, California 95655

Address all correspondence and requests for reprints to: Mohan R. Dasu, Ph.D., Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis, Medical Center, 4635, 2nd Avenue, Research Building 1, Sacramento, California 95817. E-mail: ravi.dasu{at}ucdmc.ucdavis.edu.

Toll-like receptors (TLRs) are key innate immune sensors of endogenous damage signals and play an important role in inflammatory diseases like diabetes and atherosclerosis. Pioglitazone (PIO), a peroxisome proliferator-activated receptor (PPAR)- agonist, has been reported to be an antiinflammatory agent. Thus, in the present study, we examined the antiinflammatory effects of PIO on TLR2 and TLR4 expression in human monocytes exposed to Pam3CSK4 (Pam; TLR2 ligand) and purified lipopolysaccharide (LPS; TLR4 ligand) using flow cytometry and real-time RT-PCR. Monocytes were isolated from healthy human volunteers and pretreated with PIO (1 µM) followed by Pam (170 ng/ml) and LPS (160 ng/ml) challenge. PIO significantly decreased Pam- and LPS-induced TLR2 (–56%) and TLR4 (–78%) expression (P < 0.05). In addition, PIO decreased TLR ligand-induced nuclear factor-B activity (–63%), IL-1β (–50%), IL-6 (–52%), monocyte chemoattractant protein-1(–83%), and TNF- (–87%) compared with control. Next, PIO-treated db/db mice (n = 6/group) showed decreased TLR2 (–60%) and TLR4 (–45%) expression in peritoneal macrophages compared with vehicle control mice (P < 0.001) with associated decrease in MyD88-dependent signaling and nuclear factor-B activation. Data suggest that Pam- and LPS-induced TLR2 and TLR4 expression are inhibited by PIO in human monocytes and db/db mice. Thus, we define a novel pathway by which PIO could induce antiinflammatory effects.

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