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Human Lymphatic Endothelial Cells Express Multiple Functional TLRs¹

Amarendra Pegu^*, Shulin Qin^*, Beth A. Fallert Junecko^*, Riccardo E. Nisato, Michael S. Pepper and Todd A. Reinhart^2,*

^* Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261; and Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland

The lymphatic endothelium is the preferred route for the drainage of interstitial fluid from tissues and also serves as a conduit for peripheral dendritic cells (DCs) to reach draining lymph nodes. Lymphatic endothelial cells (LECs) are known to produce chemokines that recruit Ag-loaded DCs to lymphatic vessels and therefore are likely to regulate the migration of DCs to lymph nodes. TLRs are immune receptors that recognize pathogen associated molecular patterns and then signal and stimulate production of inflammatory chemokines and cytokines that contribute to innate and adaptive immune responses. TLRs are known to be expressed by a wide variety of cell types including leukocytes, epithelial cells, and endothelial cells. Because the TLR expression profile of LECs remains largely unexamined, we have undertaken a comprehensive study of the expression of TLR1–10 mRNAs and protein in primary human dermal (HD) and lung LECs as well as in htert-HDLECs, which display a longer life-span than HDLECs. We found that all three cell types expressed TLR1–6 and TLR9. The responsiveness of these LECs to a panel of ligands for TLR1–9 was measured by real-time RT-PCR, ELISA, and flow cytometry, and revealed that the LECs responded to most but not all TLR ligands by increasing expression of inflammatory chemokines, cytokines, and adhesion molecules. These findings provide insight into the ability of cells of the lymphatic vasculature to respond to pathogens and potential vaccine adjuvants and shape peripheral environments in which DCs will acquire Ag and environmental cues.

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 grants from the National Institutes of Health (HL075845, AI060422, and AI055944).

² Address correspondence and reprint requests to Dr. Todd A. Reinhart, Department of Infectious Diseases and Microbiology, Graduate School of Public Health, 606 Parran Hall, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA 15261. E-mail address: reinhar{at}pitt.edu

³ Abbreviations used in this paper: LE, lymphatic endothelium; PAMP, pathogen-associated molecular patterns; HD, human dermal; OSM, Oncostatin M; ODN, oligodeoxynucleotides; HMVEC, human lung microvascular endothelial cell; iDC, immature DC.

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