MOLECULAR BASIS OF CELL AND DEVELOPMENTAL BIOLOGY
Surfactant Protein A Inhibits Peptidoglycan-induced Tumor Necrosis Factor-α Secretion in U937 Cells and Alveolar Macrophages by Direct Interaction with Toll-like Receptor 2*

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Pulmonary surfactant protein A (SP-A) plays an important role in modulation of the innate immune system of the lung. Peptidoglycan (PGN), a cell wall component of Gram-positive bacteria, is known to elicit excessive proinflammatory cytokine production from immune cells. In this study we investigated whether SP-A interacts with PGN and alters PGN-elicited cellular responses. Binding studies demonstrate that PGN is not a ligand for SP-A. However, SP-A significantly reduced PGN-elicited tumor necrosis factor α (TNF-α) secretion by U937 cells and rat alveolar macrophages. The inhibitory effect on TNF-α secretion was dependent upon SP-A concentrations in physiological range. Coincubation of SP-A and PGN with human embryonic kidney 293 cells that had been transiently transfected with the cDNA of Toll-like receptor 2 (TLR2), a cell signaling receptor for PGN, significantly attenuated PGN-induced nuclear factor-κB activity. SP-A directly bound to a soluble form of the recombinant extracellular TLR2 domain (sTLR2). Coincubation of sTLR2 with SP-A significantly reduced the binding of sTLR2 to PGN. These results indicate that the direct interaction of SP-A with TLR2 alters PGN-induced cell signaling. We propose that SP-A modulates inflammatory responses against the bacterial components by interactions with pattern-recognition receptors.

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Published, JBC Papers in Press, November 27, 2001, DOI 10.1074/jbc.M106671200

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This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan and from the Novartis Foundation (Japan).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.