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J. Biol. Chem., Vol. 281, Issue 42, 31448-31456, October 20, 2006

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Cell Activation of Human Macrophages by Lipoteichoic Acid Is Strongly Attenuated by Lipopolysaccharide-binding Protein^*

Mareike Mueller, Cordula Stamme^¶, Christian Draing^||, Thomas Hartung^||, Ulrich Seydel, and Andra B. Schromm^**1

From the Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Divisions of Biophysics, Cellular Pneumology, and ^**Immunobiophysics, Department of Immunochemistry and Biochemical Microbiology, D-23845 Borstel, Germany, the ^||University of Konstanz, Department of Biochemical Pharmacology, D-78457 Konstanz, Germany, and the ^¶University of Lübeck, Department of Anaesthesiology, D-23538 Lübeck, Germany

Lipoteichoic acid (LTA) represents immunostimulatory molecules expressed by Gram-positive bacteria. They activate the innate immune system via Toll-like receptors. We have investigated the role of serum proteins in activation of human macrophages by LTA from Staphylococcus aureus and found it to be strongly attenuated by serum. In contrast, the same cells showed a sensitive response to LTA and a significantly enhanced production of tumor necrosis factor under serum-free conditions. We show that LTA interacts with the serum protein lipopolysaccharide-binding protein (LBP) and inhibits the integration of LBP into phospholipid membranes, indicating the formation of complexes of LTA and soluble LBP. The addition of recombinant human LBP to serum-free medium inhibited the production of tumor necrosis factor and interleukins 6 and 8 after stimulation of human macrophages with LTA in a dose-dependent manner. Using anti-LBP antibodies, this inhibitory effect could be attributed to soluble LBP, whereas LBP in its recently described transmembrane configuration did not modulate cell activation. Also, using primary alveolar macrophages from rats, we show a sensitive cytokine response to LTA under serum-free culture conditions that was strongly attenuated in the presence of serum. In summary, our data suggest that innate immune recognition of LTA is organ-specific with negative regulation by LBP in serum-containing compartments and sensitive recognition in serum-free compartments like the lung.

Received for publication, June 22, 2006

^* This work was supported by Deutsche Forschungsgemeinschaft Grants SCHR 621/2-1 and SCHR 621/2-2, SFB 367 Project B8, and STA 609/1-3. 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: Research Center Borstel, Dept. of Immunochemistry and Biochemical Microbiology, Emmy-Noether Group Immunobiophysics, Parkallee 10, 23845 Borstel, Germany. Tel.: 49-4537-188296; Fax: 49-4537-188632; E-mail: aschromm{at}fz-borstel.de.

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