Published online before print January 3, 2008, doi: 10.1161/ATVBAHA.107.157438
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© 2008 American Heart Association, Inc.
Cell Biology/Signaling |
Wnt5A/CaMKII Signaling Contributes to the Inflammatory Response of Macrophages and Is a Target for the Antiinflammatory Action of Activated Protein C and Interleukin-10
From the Molecular and Clinical Inflammation Research Unit (C.P., D.J.S., G.S.), Medical Clinic, Department of Medicine, University Hospital of Zürich, Switzerland; Medical Clinic (E.B.B.), Uster Hospital, Uster, Switzerland; and Clinical Pathology, Department of Pathology (M.O.K.), University Hospital of Zurich, Zurich, Switzerland.
Correspondence to Gabriele Schoedon, PhD, Department of Medicine, University Hospital of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland. E-mail klinsog{at}usz.unizh.ch
Abstract
Objective— Sepsis is a major cause of death for intensive care patients. High concentrations of inflammatory cytokines are characteristic of severe systemic inflammation and activated monocytes are their predominant cellular source. To identify targets for antiinflammatory intervention, we investigated the response of human macrophages to inflammatory and antiinflammatory mediators.
Methods and Results— We profiled gene expression in human macrophages exposed to lipopolysaccharide (LPS) and interferon (IFN)-
in the presence or absence of recombinant activated protein C (APC) or IL-10 and identified Wnt5A as one of the transcripts most highly induced by LPS/IFN- and suppressed by APC and IL-10. We confirmed regulation of Wnt5A protein in macrophages and detected it in sera and bone marrow macrophages of patients with severe sepsis. We established that a functional Wnt5A/frizzled-5/CaMKII signaling pathway was essential for macrophage inflammatory activation. To prove the essential contribution of Wnt5A we measured inflammatory cytokines after stimulation with Wnt5A, silenced Wnt5A by siRNA, and blocked receptor binding with soluble Frizzled–related peptide-1 (sFRP1).
Conclusion— Wnt5A is critically involved in inflammatory macrophage signaling in sepsis and is a target for antiinflammatory mediators like APC or antagonists like sFRP1.
Gene expression profiling in human macrophages exposed to LPS and INF- in the presence or absence of recombinant APC or IL-10 identified Wnt5A as one of the most prominently regulated transcripts by these mediators. Wnt5A is critically involved in inflammatory macrophage signaling in sepsis.
Key Words: geneexpression • macrophages • activated protein C
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