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Lactate Boosts TLR4 Signaling and NF-B Pathway-Mediated Gene Transcription in Macrophages via Monocarboxylate Transporters and MD-2 Up-Regulation¹

Devadoss J. Samuvel, Kamala P. Sundararaj, Alena Nareika, Maria F. Lopes-Virella^*, and Yan Huang^2,*,

^* Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401; and Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425

It has been shown that lactate induces insulin resistance. However, the underlying mechanisms have not been well understood. Based on our observation that lactate augments LPS-stimulated inflammatory gene expression, we proposed that lactate may enhance TLR4 signaling in macrophages, which has been shown to play an important role in insulin resistance in adipocytes. In this study, we demonstrated that lactate stimulated MD-2, a coreceptor for TLR4 signaling activation, NF-B transcriptional activity, and the expression of inflammatory genes in human U937 histiocytes (resident macrophages). Similar enhancement of the inflammatory gene expression by lactate was also observed in human monocyte-derived macrophages. The essential role of MD-2 in lactate-augmented TLR4 signaling was confirmed by observation that the suppression of MD-2 expression by small interfering RNA led to significant inhibition of inflammatory gene expression. To further elucidate how lactate treatment enhances TLR4 activation, we showed that the augmentation of inflammatory gene expression by lactate was abrogated by antioxidant treatment, suggesting a critical role of reactive oxygen species in the enhancement of TLR4 activation by lactate. Finally, we showed that -cyano-4-hydroxycinnamic acid, a classic inhibitor for monocarboxylate transporters, blocked lactate-augmented inflammatory gene expression and nuclear NF-B activity, indicating that lactate transport through monocarboxylate transporters is required for lactate-enhanced TLR4 activation. Collectively, this study documents that lactate boosts TLR4 activation and NF-B-dependent inflammatory gene expression via monocarboxylate transporters and MD-2 up-regulation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant DE16353 and a Merit Review Grant from the Department of Veterans Affairs (to Y.H.).

² Address correspondence and reprint requests to Dr. Yan Huang, Ralph H. Johnson Veterans Affairs Medical Center, and Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, 114 Doughty St. Charleston, SC 29403. E-mail address: huangyan{at}musc.edu

³ Abbreviations used in this paper: MCT, monocarboxylate transporter; -CHCA, -cyano-4-hydroxycinnamic acid; COX2, cyclooxygenase 2; HMDM, human monocyte-derived macrophage; NAC, N-acetyl-L-cysteine; ROS, reactive oxygen species; siRNA, small interfering RNA.

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The JI 2009 182: 1777-1778. [Full Text]