Regulation of c-Jun N-terminal kinase and p38 kinase pathways in endothelial cells

Raj Wadgaonkar, Jacqueline W. Pierce, Kaumudi Somnay, Rachel L. Damico, Michael T. Crow, Tucker Collins, Joe G.N. Garcia

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

The rapid and transient induction of E-selectin gene expression by inflammatory tumor necrosis factor (TNF)-α in endothelial cells is mediated by signaling pathways which involve c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) kinase pathways. To explore this regulation, we first observed that in the continuous presence of cytokine TNF, activation of JNK-1 in both nuclear and cytoplasmic compartments peaked at 15-30 min, with activity returning to uninduced levels by 60 min. Phosphorylation of both the p38 kinase and its molecular target, the nuclear transcription factor, activating transcription factor-2, were transient after TNF-α or interleukin (IL)-1β induction. However, cycloheximide treatment prolonged the TNF-α-induced JNK-1 kinase activity beyond 60 min, suggesting that protein synthesis is required to limit this signaling cascade. We investigated the possible role of the dual-specificity phosphatases MAPK phosphatase (MKP)-1 and MKP-2 in limiting cytokine-induced MAPK signaling. Maximum induction of MKP-1 mRNA and nuclear protein levels by TNF-α or IL-1β were noted at 60 min and their expression correlated with the termination of JNK kinase activity, whereas nuclear levels of MKP-2 were not significantly affected by treatment with TNF-α or IL-1β. Transient overexpression of MKP-1 demonstrated significant specific inhibition of E-selectin promoter activity consistent with a regulatory role for dual-specificity phosphatases. Inhibition of MKP-1 expression through the use of small interfering RNAs prolonged the cytokine-induced p38 and JNK kinase phosphorylation. Our results suggest that endogenous inhibitors of the MAPK cascade, such as the dual-specificity phosphatases like MKP-1 may be important for the postinduction repression of MAPK activity and E-selectin transcription in endothelial cells. Thus, these inhibitors may play an important role in limiting the inflammatory effects of TNF-α and IL-1β.

Original languageEnglish (US)
Pages (from-to)423-431
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume31
Issue number4
DOIs
StatePublished - Oct 2004
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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