HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/C1140    most recent 00071.2009v1 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 Google Scholar Google Scholar Articles by Goring, K. Articles by Winston, B. W. Search for Related Content PubMed PubMed Citation Articles by Goring, K. Articles by Winston, B. W.

RECEPTORS AND SIGNAL TRANSDUCTION

Mechanisms of human complement factor B induction in sepsis and inhibition by activated protein C

¹Departments of Medicine, ²Biochemistry and Molecular Biology, and ³Critical Care Medicine; and ⁴Physiology and Biophysics and ⁵Immunology Research Group, University of Calgary, Calgary, Alberta, Canada

Submitted 13 February 2009 ; accepted in final form 4 March 2009

To investigate the potential role of the local expression of alternative complement factor B (hBf) in human sepsis, we examined the induction of Bf gene expression in human peripheral blood monocytes (PBMCs) from patients with septic shock and the mechanisms of hBf gene regulation by tumor necrosis factor (TNF)-, interferon (IFN)-, and lipopolysaccharide (LPS) in human monocytes. PBMCs from septic shock patients showed increased hBf mRNA expression when compared with control patients. Costimulation with TNF- and IFN- or stimulation with LPS demonstrated a time- and dose-dependent induction of hBf mRNA expression in human PBMCs. A region of the hBf promoter between –735 and +128 bp was found to mediate IFN-, TNF-, and LPS responsiveness as well as the synergistic effect of IFN-/TNF- on hBf promoter activity. Site-directed mutagenesis of a IFN--activation site (GAS) cis element (–90 to –82 bp) abrogated IFN- responsiveness. Mutagenesis of a nuclear factor (NF)-B cis element at –466 to –456 bp abrogated TNF- and LPS responsiveness of the Bf promoter. Thus hBf gene expression is induced in PBMCs from septic shock patients, and the induction of hBf by IFN-, TNF-, and LPS is through GAS and NF-B cis-binding sites on the hBf promoter. Furthermore, activated protein C (APC) inhibited LPS-stimulated hBf promoter activity and protein expression in human monocytes suggesting that the beneficial effect of APC therapy in sepsis may in part be due to inhibition of complement induction and/or activation via the alternative pathway.

septic shock; monocytes/macrophages; complement factor B; cytokines