Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 31, Issue 4, Pages 423-431Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2003-0384OC
Keywords
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Funding
- NHLBI NIH HHS [P01 HL 36028, HL 58064, HL 35716] Funding Source: Medline
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The rapid and transient induction of E-selectin gene expression by inflammatory tumor necrosis factor (TNF)-alpha in endothelial cells is mediated by signaling pathways which involve c-Jun N-terminal kinase (INK) 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-alpha or interleukin (IL)-1beta induction. However, cycloheximide treatment prolonged the TNF-alpha-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-a or IL-1beta were noted at 60 min and their expression correlated with the termination of INK kinase activity, whereas nuclear levels of MKP-2 were not significantly affected by treatment with TNF-alpha or IL-1beta. 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 INK 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-alpha and IL-1beta.
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