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Am J Physiol Lung Cell Mol Physiol (March 15, 2002). doi:10.1152/ajplung.00060.2002
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Articles in PresS, published online ahead of print March 15, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00060.2002
Submitted on February 13, 2002
Accepted on March 7, 2002

Regulation of Human Airway Epithelial Cell Interleukin-8 Expression by Mitogen-Activated Protein Kinases

Jing Li1, Sreedharan Kartha1, Svetlana Iasvovskaia1, Alan Tan1, Rajesh K. Bhat1, Joel M. Manaligod1, Kristen Page1, Allan R. Brasier2, and Marc B. Hershenson1*

1 Pediatrics, University of Chicago, Chicago, IL, USA
2 Medicine, University of Texas Medical Branch, Galveston, TX, USA

* To whom correspondence should be addressed. E-mail: mhershen{at}midway.uchicago.edu.

Maximal interleukin (IL)-8 protein expression requires activation of nuclear factor (NF)-{kappa}B and the mitogen-activated protein (MAP) kinases extracellular signal regulated kinase (ERK), Jun amino terminal kinase (JNK) and p38. However, the precise relationship between NF-{kappa}B and MAP kinase activation remains unclear. We examined the requirements of NF-{kappa}B, ERK, JNK and p38 for tumor necrosis factor-alpha (TNF{alpha})-induced transcription from the IL-8 promoter in a human bronchial epithelial cell line. Treatment with TNF{alpha} activated all three MAP kinases. Inhibition of NF-{kappa}B, ERK and JNK, but not p38, each decreased TNF{alpha}-induced IL-8 promoter activity. Inhibition of JNK signaling reduced TNF{alpha}-induced NF-{kappa}B transactivation, whereas inhibition of ERK and p38 had no effect. ERK was required and sufficient for TNF{alpha}-induced activation of AP-1 promoter sequences, which function as a basal level enhancer. JNK activation was also required for AP-1 transactivation. Finally, inhibition of p38 attenuated IL-8 protein abundance. We conclude that, in human airway epithelial cells, MAP kinases regulate IL-8 promoter activity by NF-{kappa}B-dependent (in the case of JNK) and -independent (ERK) processes, as well as by post-transcriptional mechanisms (p38).




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