Pulmonary Surfactant Protein D Inhibits Lipopolysaccharide (LPS)‐Induced Inflammatory Cell Responses by Altering LPS Binding to Its Receptors

Abstract

Pulmonary sufactant protein D (SP‐D), member of the collectin family, plays an important role in regulating innate immunity of the lung. We examined the mechanisms by which SP‐D modulates lipopolysaccharide (LPS)‐elicited inflammatory cell responses. SP‐D bound to a complex of Toll‐like receptor 4 (TLR4) and MD‐2, and down‐regulated TNF‐α secretion and NF‐κB activation elicited by LPS, in alveolar macrophages and TLR4/MD‐2‐transfected HEK293 cells. Cell surface binding of LPS to TLR4/MD‐2‐expressing cells was attenuated by SP‐D. In addition, SP‐D significantly reduced MD‐2 binding to both serotypes of LPS. A chimera containing the amino‐terminal region and the collagenous domain of surfactant protein A, and the coiled‐coil neck and lectin domains of SP‐D, was a weak inhibitor of LPS‐induced cell responses and MD‐2 binding to LPS, compared to native SP‐D. The collagenase‐resistant fragment consisting of the neck plus the carbohydrate recognition domain of SP‐D also was a very weak inhibitor of LPS activation. This study demonstrates that SP‐D down‐regulates LPS‐elicited inflammatory responses by altering LPS binding to its receptors, and reveals the importance of the correct oligomeric structure of the protein in this process.This works was supported in part by a Grant‐in‐Aid for scientific research from the MEXT, Japan.