APStracts 10:0100L, 2003.

Stretch-induced IL-8 depends on c-Jun NH2-terminal and nuclear factor-?B-inducing kinases. Li, Li-Fu, Bin Ouyang, Gabriel Choukroun,, Robina Matyal, Marcella Mascarenhas, Behrouz Jafari, Joseph V. Bonventre, Thomas Force, and Deborah A. Quinn. 1Pulmonary and Critical Care and Renal Units, Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston 02114; 4Molecular Cardiology Research Institute, Tufts New England Medical Center and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111; 2Chang Gung University, Tao-Yuan 333, Taiwan; and 3Internal Medicine and Nephrology Department, Amiens Hospital, France
APStracts 10:0100L, 2003.
Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including interleukin (IL)-8. The mechanisms regulating lung stretch- induced cytokine production are unclear. We hypothesized that stretch-induced IL-8 production is dependent on the activation of the mitogen-activated protein kinases, c-Jun NH2-terminal kinases (JNK), p38, and/or extracellular signal-regulated kinase (ERK) 1/2. We exposed A549 cells, a type II-like alveolar epithelial cell line, to cyclic stretch at 20 cycles/min for 5 min--2 h. Cyclic stretch induced IL-8 protein production, IL-8 mRNA expression, and JNK activation, but only transient activation of p38 and ERK1/2. Inhibition of stretch-induced JNK activation by adenovirus-mediated gene transfer of SEK-1, a dominant inhibitory mutant of SEK-1, the immediate upstream activator of the JNKs, and pharmacological JNK inhibitor II SP-600125 blocked IL-8 mRNA expression and attenuated IL-8 production. Inhibition of p38 and ERK1/2 did not affect stretch-induced IL-8 production. Stretch-induced activation NF-?B and activator protein (AP)-1 was blocked by NF-?B inhibitor and JNK inhibitor, respectively. An NF-IL-6 site was not essential for cyclic stretch-induced IL-8 promoter activity. Stretch also induced NF-?B-inducing kinase (NIK) activation, and inhibition of NF-?B attenuated IL-8 mRNA expression and IL-8 production. We conclude that stretch- induced transcriptional regulation of IL-8 mRNA and IL-8 production was via activation of AP-1 and NF-?B and was dependent on JNK and NIK activation, respectively.

Received 31 January 2003; accepted in final form 21 April 2003
APS Manuscript Number L31-3.
Article publication pending Am J Physiol Lung Cell Mol Physiol
ISSN 1080-4757 Copyright 2003 The American Physiological Society.
Published in APStracts on 30 May 2003