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Increased Toll-Like Receptor (TLR) 2 and TLR4 Expression in Monocytes from Patients with Type 1 Diabetes: Further Evidence of a Proinflammatory State

Laboratory for Atherosclerosis and Metabolic Research (S.D., M.R.D., J.R., I.J.), Department of Pathology and Internal Medicine (S.C.G., I.J.), University of California Davis Medical Center, Sacramento, California 95817; and Department of Pathology (W.W.), University of Florida at Gainesville, Gainesville, Florida 32611

Address all correspondence and requests for reprints to: I. Jialal, M.D., Ph.D., Director, Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, 4635 II Avenue, Research I Building, Room 3000, Sacramento, California 95817. E-mail: ijialal{at}ucdavis.edu.

Context: Type 1 diabetes (T1DM) is associated with increased cardiovascular mortality. It is a pro-inflammatory state as evidenced by increased circulating biomarkers and monocyte activity. The toll-like receptors (TLRs) are pattern recognition receptors, expressed abundantly on monocytes. TLR2 and TLR4 are important in atherosclerosis. However, there is a paucity of data examining TLR2 and TLR4 expression in T1DM and examining its contribution to the proinflammatory state.

Objective: Thus, we examined TLR2 and TLR4 expression in monocytes from T1DM patients compared with controls (n = 31 per group).

Setting: The study was performed at the University of California Davis Medical Center.

Patients: Healthy controls (n = 31) and T1DM patients (n = 31) were included in the study.

Results: TLR2 and TLR4 surface expression and mRNA were significantly increased in T1DM monocytes compared with controls. Downstream targets of TLR, nuclear factor B, myeloid differentiation factor 88, Trif, and phosphorylated IL-1 receptor-associated kinase were significantly up-regulated in T1DM. Finally, the release of IL-1β and TNF- was significantly increased in monocytes from T1DM compared with controls and correlated with TLR2 and TLR4 expression (P < 0.005). In addition, TLR2 and TLR4 expression was significantly correlated to glycosylated hemoglobin, carboxymethyllysine, and nuclear factor B (P < 0.02).

Conclusion: Thus, we make the novel observation that TLR2 and TLR4 expression and signaling are increased in T1DM and contribute to the proinflammatory state.

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