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in I
B-
-Dependent Anti-Inflammatory Immune Regulation1
* Department of Immunochemistry and Biochemical Microbiology, Division of Cellular Pneumology, Research Center Borstel, Leibniz Center for Medicine and Bioscience, Borstel, Germany;
Department of Immunology and Cell Biology, Division of Veterinary Infection Biology and Immunology, Research Center Borstel, Leibniz Center for Medicine and Bioscience, Borstel, Germany;
Emmy-Noether Group Immunobiophysics, Research Center Borstel, Leibniz Center for Medicine and Bioscience, Borstel, Germany;
Biotechnolgy Centre of Oslo, University of Oslo, Oslo, Norway; and
¶ Department of Anesthesiology, University Hospital of Lübeck, Lübeck, Germany
The pulmonary collectin surfactant protein (SP)-A has a pivotal role in anti-inflammatory modulation of lung immunity. The mechanisms underlying SP-A-mediated inhibition of LPS-induced NF-
B activation in vivo and in vitro are only partially understood. We previously demonstrated that SP-A stabilizes IB-
, the primary regulator of NF-B, in alveolar macrophages (AM) both constitutively and in the presence of LPS. In this study, we show that in AM and PBMC from IB- knockout/IB-
knockin mice, SP-A fails to inhibit LPS-induced TNF- production and p65 nuclear translocation, confirming a critical role for IB- in SP-A-mediated LPS inhibition. We identify atypical (a) protein kinase C (PKC) 
as a pivotal upstream regulator of SP-A-mediated IB-/NF-B pathway modulation deduced from blocking experiments and confirmed by using AM from PKC–/– mice. SP-A transiently triggers aPKCThr410/403 phosphorylation, aPKC kinase activity, and translocation in primary rat AM. Coimmunoprecipitation experiments reveal that SP-A induces aPKC/p65 binding under constitutive conditions. Together the data indicate that anti-inflammatory macrophage activation via IB- by SP-A critically depends on PKC activity, and thus attribute a novel, stimulus-specific signaling function to PKC in SP-A-modulated pulmonary immune response.
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 This work was supported by the Deutsche Forschungsgemeinschaft 609/1-3 and 609/1-4 (to C.S.) and 621/2-2 (to A.B.S.).
2 Address correspondence and reprint requests to Dr. Cordula Stamme, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany. E-mail address: cstamme{at}fz-borstel.de
3 Abbreviations used in this paper: SP, surfactant protein; AKBI, IB- knockout/IB- knockin; AM, alveolar macrophage; aPKC, atypical protein kinase C; cPKC, classical protein kinase C; DAG, diacylglycerol; HI, heat inactivated; IKK, IB kinase; PKC, protein kinase C; ps, pseudosubstrate; wt, wild type.
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