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Accumulation of Inhibitory B- as a Mechanism Contributing to the Anti-Inflammatory Effects of Surfactant Protein–A

Department of Anesthesiology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Departments of Immunochemistry and Biochemical Microbiology, and of Immunology and Cell Biology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel; Institute of Microbiology and Hygiene, Charité, Humboldt University Berlin, Berlin; and Department of Anesthesiology, University of Lübeck, Lübeck, Germany

Address correspondence to: Cordula Stamme, M.D., Dept. of Immunochemistry and Biochemical Microbiology, Research Center Borstel, Parkallee 22, 23845 Borstel, Germany. E-mail: cstamme{at}fz-borstel.de

The collectin surfactant protein (SP)-A has been implicated in multiple immunoregulatory functions of innate pulmonary host defense via modulating immune responses both in vitro and in vivo. The aim of the present study was to investigate mechanisms responsible for the anti-inflammatory effects of human (hu) SP-A on the inhibitory B (IB)/nuclear factor (NF)-B signaling pathway in alveolar macrophages (AMs). Initial CD25 expression analysis by flow cytometry of CD14/hu Toll-like receptor 4–transfected Chinese hamster ovary reporter cells demonstrated that SP-A alone does not induce any NF-B–dependent CD25 expression in these cells. In AMs, SP-A pretreatment caused a marked inhibition of lipopolysaccharide (LPS)-induced NF-B activation independent of the LPS chemotype used as determined by electrophoretic mobility shift assay. Western blot analysis revealed that SP-A by itself increased the protein expression of IB-, the predominant regulator for rapidly induced NF-B, in a dose- and time-dependent manner without enhancing IB- messenger RNA as determined by reverse transcription-polymerase chain reaction. SP-A did not interfere with LPS-induced serine³² phosphorylation of IB- but significantly enhanced IB- abundance under LPS-coupled conditions. The data suggest that anti-inflammatory effects of SP-A on LPS-challenged AMs are associated with a SP-A-mediated direct modulation of the IB- turnover in these cells.

Abbreviations: antibody, Ab • alveolar macrophages, AMs • Chinese hamster ovary, CHO • casein kinase II, CKII • electrophoretic mobility shift assay, EMSA • fetal calf serum, FCS • heat-inactivated, HI • horseradish peroxidase, HRP • human, hu • immunoglobulin, Ig • inhibitory B, IB • IB kinase, IKK • interleukin, IL • lipopolysaccharide, LPS • nuclear factor, NF • proteasome inhibitor, PSI • reverse transcription–polymerase chain reaction, RT-PCR • rough LPS, R-LPS • smooth LPS, S-LPS • serine residue, Ser • surfactant protein A, SP-A • human monocytic leukemic cell line, THP-1 • Toll-like receptor, TLR • tumor necrosis factor, TNF

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