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J. Biol. Chem., Vol. 282, Issue 11, 8134-8141, March 16, 2007

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Pathogen Recognition by Toll-like Receptor 2 Activates Weibel-Palade Body Exocytosis in Human Aortic Endothelial Cells^*

Takeshi Into¹, Yosuke Kanno, Jun-ichi Dohkan, Misako Nakashima, Megumi Inomata, Ken-ichiro Shibata, Charles J. Lowenstein^¶, and Kenji Matsushita

From the Department of Oral Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan, the Laboratory of Oral Molecular Microbiology, Department of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan, and the ^¶Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

The endothelial cell-specific granule Weibel-Palade body releases vasoactive substances capable of modulating vascular inflammation. Although innate recognition of pathogens by Toll-like receptors (TLRs) is thought to play a crucial role in promotion of inflammatory responses, the molecular basis for early-phase responses of endothelial cells to bacterial pathogens has not fully been understood. We here report that human aortic endothelial cells respond to bacterial lipoteichoic acid (LTA) and synthetic bacterial lipopeptides, but not lipopolysaccharide or peptidoglycan, to induce Weibel-Palade body exocytosis, accompanied by release or externalization of the storage components von Willebrand factor and P-selectin. LTA could activate rapid Weibel-Palade body exocytosis through a TLR2- and MyD88-dependent mechanism without de novo protein synthesis. This process was at least mediated through MyD88-dependent phosphorylation and activation of phospholipase C. Moreover, LTA activated interleukin-1 receptor-associated kinase-1-dependent delayed exocytosis with de novo protein synthesis and phospholipase C-dependent activation of the NF-B pathway. Increased TLR2 expression by transfection or interferon- treatment increased TLR2-mediated Weibel-Palade body exocytosis, whereas reduced TLR2 expression under laminar flow decreased the response. Thus, we propose a novel role for TLR2 in induction of a primary proinflammatory event in aortic endothelial cells through Weibel-Palade body exocytosis, which may be an important step for linking innate recognition of bacterial pathogens to vascular inflammation.

Received for publication, October 24, 2006 , and in revised form, December 22, 2006.

^* This work was supported by a Grant-in-aid for Young Scientists ((B):18791363 to T. I.) provided by the Ministry of Education, Culture, Sports, Science and Technology and by Mitsui, Life Social Welfare Foundation, Aich Cancer Research Foundation, Mitsubishi Pharma Research Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Suzuken Memorial Foundation (to K. M.). 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 To whom correspondence should be addressed. Tel.: 81-562-44-5651; Fax: 81-562-46-8684; E-mail: into{at}nils.go.jp.

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				T. Into, M. Inomata, M. Nakashima, K.-i. Shibata, H. Hacker, and K. Matsushita Regulation of MyD88-Dependent Signaling Events by S Nitrosylation Retards Toll-Like Receptor Signal Transduction and Initiation of Acute-Phase Immune Responses Mol. Cell. Biol., February 15, 2008; 28(4): 1338 - 1347. [Abstract] [Full Text] [PDF]

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