Weber Nina C, Blumenthal Signe B, Hartung Thomas, Vollmar Angelika M, Kiemer Alexandra K
Department of Pharmacy, University of Munich, Germany.
J Leukoc Biol. 2003 Nov;74(5):932-41. doi: 10.1189/jlb.0603254. Epub 2003 Aug 11.
Atrial natriuretic peptide (ANP) has been shown to reduce tumor necrosis factor-alpha (TNF-alpha)-induced activation of endothelial cells via inhibition of p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB pathways. The aim of this study was to determine whether ANP is able to inhibit TNF-alpha-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-alpha-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-alpha-induced expression of MCP-1. To investigate a potential interplay between TNF-alpha-induced activation of p38 MAPK and NF-kappaB, 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-kappaB and therefore, suggest a counter-regulatory action of p38 MAPK and NF-kappaB. 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-kappaB inhibition.
心房利钠肽（ANP）已被证明可通过抑制p38丝裂原活化蛋白激酶（MAPK）和核因子（NF）-κB途径，减少肿瘤坏死因子-α（TNF-α）诱导的内皮细胞活化。本研究的目的是确定ANP是否能够抑制TNF-α诱导的内皮细胞单核细胞趋化蛋白-1（MCP-1）表达，并阐明其中涉及的机制。用ANP预处理人脐静脉内皮细胞（HUVEC）可显著降低TNF-α诱导的MCP-1蛋白和mRNA表达。结果表明，ANP的作用是通过鸟苷酸环化酶（GC）偶联的A受体介导的。C型利钠肽激活另一种GC偶联受体（利钠肽受体-B）以及用S-亚硝基-L-谷胱甘肽（GSNO）激活可溶性GC，产生了与ANP类似的作用，支持环磷酸鸟苷（cGMP）在信号转导中的作用。反义实验表明，在ANP介导的TNF-α诱导的MCP-1表达抑制中，需要诱导丝裂原活化蛋白激酶磷酸酶-1（MKP-1），因此需要抑制p38 MAPK。为了研究TNF-α诱导的p38 MAPK和NF-κB激活之间的潜在相互作用，使用了p38 MAPK抑制剂SB203580和显性负性p38 MAPK突变体。结果表明，阻断p38 MAPK活性会导致NF-κB激活增加，因此提示p38 MAPK和NF-κB存在反向调节作用。由于反义实验揭示了MKP-1诱导以及p38 MAPK抑制在ANP介导的MCP-1表达减弱中的关键作用，这种作用似乎相当独立于NF-κB抑制。
