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Anti endothelial cell autoantibodies selectively activate SAPK/JNK signalling in Wegener's granulomatosis.

Abstract
The pathogenic role of anti-endothelial cell antibodies (AECA) in vascular injury is debated. It was previously shown that many patients with Wegener's granulomatosis (WG) have AECA that react with human kidney microvascular endothelial cells (EC). In addition, during active disease, renal endothelium strongly expresses the inflammatory molecules vascular adhesion protein-1 (VAP-1) and MHC class I-related antigen A (MICA). This study sought to determine whether AECA mediates this upregulation of VAP-1 and MICA and to define better the signaling pathways that are activated by these autoantibodies upon binding to EC in the kidney. Stimulation of human kidney microvascular EC with AECA IgG upregulated surface expression of MICA and VAP-1, elicited a rapid Ca2+ flux, induced high levels of the chemokines monocyte chemoattractant protein-1 and granulocyte chemotactic protein-2, induced specific phosphorylation of stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and the transcription factors c-Jun and activating transcription factor-2, and activated NF-kappaB. Specific inhibitors of SAPK/JNK significantly reduced AECA-induced chemokine production and phosphorylation of c-Jun and activating transcription factor-2 and abrogated protein expression of MICA but not VAP-1. In kidney sections from patients with WG, infiltrating cells that expressed the ligand for MICA (NKG2D+) were identified, as were CD8+ and 32 gamma delta+ T cells. In conclusion, AECA may be involved in the pathogenesis of WG, and the SAPK/JNK pathway and the endothelial inflammatory protein VAP-1 may be novel therapeutic targets for vasculitis.
AuthorsCarolina Holmén, Elzafir Elsheikh, Marta Christensson, Jining Liu, Anne-Sofie Johansson, Abdul Rashid Qureshi, Sirpa Jalkanen, Suchitra Sumitran-Holgersson
JournalJournal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 18 Issue 9 Pg. 2497-508 (Sep 2007) ISSN: 1046-6673 [Print] United States
PMID17699811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens
  • Autoantibodies
  • Cell Adhesion Molecules
  • Chemokines
  • Histocompatibility Antigens Class I
  • Immunoglobulin G
  • MHC class I-related chain A
  • AOC3 protein, human
  • Amine Oxidase (Copper-Containing)
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Myeloblastin
Topics
  • Aged
  • Aged, 80 and over
  • Amine Oxidase (Copper-Containing) (metabolism)
  • Antigens (immunology)
  • Autoantibodies (immunology, metabolism)
  • Cell Adhesion Molecules (metabolism)
  • Cells, Cultured
  • Chemokines (metabolism)
  • Endothelial Cells (immunology)
  • Enzyme Activation (drug effects)
  • Female
  • Granulomatosis with Polyangiitis (immunology, metabolism)
  • Histocompatibility Antigens Class I (metabolism)
  • Humans
  • Immunoglobulin G (chemistry, immunology, pharmacology)
  • JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
  • Kidney (blood supply, metabolism)
  • MAP Kinase Signaling System
  • Male
  • Microcirculation
  • Middle Aged
  • Mitogen-Activated Protein Kinases (metabolism)
  • Myeloblastin (deficiency)
  • Up-Regulation

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