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* Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Center for Molecular Medicine, Austrian Academy of Sciences and
Division of Infectious Diseases, Department of Internal Medicine 1, Medical University of Vienna, Vienna, Austria;
Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
¶ Biochemical Pharmacology, University of Konstanz, Konstanz, Germany; and
|| Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605
Lipoteichoic acid (LTA) is a major outer cell wall component of Gram-positive bacteria that has been implicated as an important factor in the inflammatory response following bacterial infection. In vitro data indicate roles for TLR2, platelet-activating factor receptor (PAFR), CD14, and LPS-binding protein (LBP) in cellular responsiveness to LTA, whereas the mechanisms contributing to LTA effects in vivo have never been investigated. Using mice deficient for LBP, CD14, TLR2, TLR4, or PAFR, we now examined the role of these molecules in pulmonary inflammation induced by highly purified LTA in vivo. Although pulmonary LBP increased dose-dependently following administration of LTA, the inflammatory response was unaltered in LBP–/– mice. TLR2 proved to be indispensable for the initiation of an inflammatory response, as polymorphonuclear cell influx, TNF-
, keratinocyte-derived chemokine, and MIP-2 release were abolished in TLR2–/– mice. Minor effects such as moderately decreased TNF- and MIP-2 levels were observed in the absence of CD14, indicating a role for CD14 as a coreceptor. Quite surprisingly, the absence of TLR4 greatly diminished pulmonary inflammation and the same phenotype was observed in PAFR–/– animals. In contrast to all other mice studied, only TLR4–/– and PAFR–/– mice displayed significantly elevated IL-10 pulmonary concentrations. These data suggest that TLR2 is the single most important receptor signaling the presence of LTA within the lungs in vivo, whereas TLR4 and PAFR may influence lung inflammation induced by LTA either by sensing LTA directly or through recognition and signaling of endogenous mediators induced by the interaction between LTA and TLR2.
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 Address correspondence and reprint requests to Dr. Sylvia Knapp, Division of Infectious Diseases, Department of Internal Medicine 1, Center for Molecular Medicine of the Austrian Academy of Sciences, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail address: sylvia.knapp{at}meduniwien.ac.at
2 Abbreviations used in this paper: LTA, lipoteichoic acid; PMN, polymorphonuclear cell; LBP, LPS-binding protein; PAFR, platelet-activating factor receptor; BAL, bronchoalveolar lavage; BALF, BAL fluid; AM, alveolar macrophage; HEK, human embryonic kidney; i.n., intranasal(ly); KC, keratinocyte-derived chemokine; MPO, myeloperoxidase; n.s., not significant.
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