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Published ahead of print on July 1, 2004, doi:10.1165/rcmb.2003-0384OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 4, October 2004, 423-431

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Submitted on October 28, 2003
Revised on June 25, 2004

Regulation of c-JUN N-terminal Kinase and p38 Kinase Pathways in Endothelial Cells

Raj Wadgaonkar1*, Jacqueline W Pierce2, Kaumudi Somnay3, Rachel L Damico1, Michael T Crow1, Tucker Collins2, and Joe G.N. Garcia1

1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA, 2 Children's Hospital and Harvard Medical School, Boston, MA, USA, 3 Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: rwadgao1{at}jhem.jhmi.edu.

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 (JNK) and p38 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 ATF-2, were transient following TNF{alpha} or interleukin-1 beta (IL-1{beta}) 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 MAP kinase phosphatase-1 (MKP-1) and MAP kinase phosphatase 2 (MKP-2), in limiting cytokine-induced MAP kinase signaling. Maximum induction of MKP-1 mRNA and nuclear protein levels by TNF{alpha} or IL-1{beta} 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{alpha} or IL-1{beta}. 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 MAP kinase cascade such as the dual specificity phosphatases MKP-1 may be important for the post-induction repression of MAP kinase activity and E-selectin transcription in endothelial cells and thus may play an important role in limiting the inflammatory effects of TNF{alpha} and IL-1{beta}.




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