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ANP inhibits TNF‐α‐induced endothelial MCP‐1 expression—involvement of p38 MAPK and MKP‐1
Author(s) -
Weber Nina C.,
Blumenthal Signe B.,
Hartung Thomas,
Vollmar Angelika M.,
Kiemer Alexandra K.
Publication year - 2003
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0603254
Subject(s) - mapk/erk pathway , p38 mitogen activated protein kinases , protein kinase a , biology , tumor necrosis factor alpha , signal transduction , umbilical vein , atrial natriuretic peptide , cyclic guanosine monophosphate , endocrinology , medicine , pertussis toxin , microbiology and biotechnology , kinase , nitric oxide , g protein , biochemistry , in vitro
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.