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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/L430    most recent 90458.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Moulakakis, C. Articles by Stamme, C. Search for Related Content PubMed PubMed Citation Articles by Moulakakis, C. Articles by Stamme, C.

Role of clathrin-mediated endocytosis of surfactant protein A by alveolar macrophages in intracellular signaling

¹Department of Clinical Medicine, Division of Cellular Pneumology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel; and ²Department of Anesthesiology, University Hospital of Lübeck, Lübeck, Germany

Submitted 25 August 2008 ; accepted in final form 2 January 2009

We recently provided evidence that anti-inflammatory macrophage activation, i.e., the inhibition of constitutive and signal-induced NF-B activity by the pulmonary collectin surfactant protein (SP)-A, critically involves a promoted stabilization of IB-, the predominant inhibitor of NF-B, via posttranscriptional mechanisms comprising the activation of atypical (a)PKC. SP-A uptake and degradation by alveolar macrophages (AM) occur in a receptor-mediated, clathrin-dependent manner. However, a mutual link between endocytosis of and signaling by SP-A remains elusive. The aim of this study was to investigate whether clathrin-mediated endocytosis (CME) of SP-A by AM is a prerequisite for its modulation of the IB-/NF-B pathway. The inhibition of clathrin-coated pit (CCP) formation and clathrin-coated vesicle (CCV) formation/budding abrogates SP-A-mediated IB- stabilization and SP-A-mediated inhibition of LPS-induced NF-B activation in freshly isolated rat AM, as determined by Western analysis, fluorescence-activated cell sorting, confocal microscopy, and EMSA. Actin depolymerization and inhibition of CCP formation further abolished SP-A-mediated inhibition of LPS-induced TNF- release, as determined by ELISA. In addition, SP-A-induced atypical PKC activation was abolished by pretreatment of AM with CCV inhibitors as determined by in vitro immunocomplex kinase assay. Although CME is classically considered as a means to terminate signaling, our results demonstrate that SP-A uptake via CME by AM has to precede the initiation of SP-A signaling.

collectins; lung; lipopolysaccharide; nuclear factor-B; protein kinase C