ANP inhibits TNF-α-induced endothelial MCP-1 expression involvement of p38 MAPK and MKP-1

Nina C. Weber, Signe B. Blumenthal, Thomas Hartung, Angelika M. Vollmar, Alexandra K. Kiemer

Research output: Contribution to journalArticle

Abstract

Atrial natriuretic peptide (ANP) has been shown to reduce tumor necrosis factor-α (TNF-α)-induced activation of endothelial cells via inhibition of p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB pathways. The aim of this study was to determine whether ANP is able to inhibit TNF-α-induced expression of monocyte chemoattractant protein-1 (MCP-1) in endothelial cells and to elucidate the mechanisms involved. Pretreatment of human umbilical vein endothelial cells (HUVEC) with ANP significantly reduced TNF-α-induced expression of MCP-1 protein and mRNA. The effects of ANP were shown to be mediated via the guanylyl-cyclase (GC)-coupled A receptor. Activation of the other GC-coupled receptor (natriuretic peptide receptor-B) by the C-type natriuretic peptide as well as activation of soluble GC with S-nitroso-L-glutathione (GSNO) exerted similar effects as ANP, supporting a role for cyclic guanosine monophosphate (cGMP) in the signal transduction. Antisense experiments showed a requirement of MAPK phosphatase-1 (MKP-1) induction and therefore, inhibition of p38 MAPK in the ANP-mediated inhibition of TNF-α-induced expression of MCP-1. To investigate a potential interplay between TNF-α-induced activation of p38 MAPK and NF-κB, the p38 MAPK inhibitor SB203580 and a dominant-negative p38 MAPK mutant were used. The results indicated that the blockade of p38 MAPK activity leads to an increased activation of NF-κB and therefore, suggest a counter-regulatory action of p38 MAPK and NF-κB. As antisense experiments revealed a pivotal role for MKP-1 induction and therefore, p38 MAPK inhibition in ANP-mediated attenuation of MCP-1 expression, this action seems to be rather independent of NF-κB inhibition.

Original languageEnglish (US)
Pages (from-to)932-941
Number of pages10
JournalJournal of Leukocyte Biology
Volume74
Issue number5
DOIs
StatePublished - Nov 1 2003
Externally publishedYes

Keywords

  • Atherosclerosis
  • Chemokines
  • Cytokines
  • Endothelial cells
  • Inflammation
  • Natruiretic peptides

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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