Published ahead of print on September 13, 2007, doi:10.1165/rcmb.2007-0172OC Am. J. Respir. Cell Mol. Biol., Volume 38, Number 2, February 2008, 239-246 A more recent version of this article appeared on February 1, 2008
Submitted on May 15, 2007 Effects of KGF on Alveolar Epithelial Cell Transdifferentiation are Mediated by JNK SignalingRenli Qiao1*,1 University of Southern California, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and Critical Care Medicine, Los Angeles, CA, USA, 2 Bioinformatics User Facility, University of California Los Angeles, Angeles, CA, USA, 3 Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, CA, USA, 4 Microarray Center, University of Southern California, Institute for Genetic Medicine, Los Angeles, CA, USA * To whom correspondence should be addressed. E-mail: rqiao{at}usc.edu.
Rat alveolar epithelial cells (AEC) in primary culture transdifferentiate from a type II (AT2) towards a type I (AT1) cell-like phenotype, a process that can be both prevented and reversed by keratinocyte growth factor (KGF). Microarray analysis revealed that these effects of KGF are associated with upregulation of key molecules in the mitogen-activated protein kinase (MAPK) pathway. To further explore the role of three key MAPK (i.e., extracellular signal-related kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK) and p38) in mediating effects of KGF on alveolar epithelial cell (AEC) phenotype, primary rat AEC cultivated in minimal defined serum-free medium (MDSF) were treated with KGF (10 ng/ml) from Day 4 for intervals up to 48 hr. Exposure to KGF activated all three MAPK, with activation of ERK1/2 and p38 MAPK preceding that of JNK. Inhibition of JNK, but not of ERK1/2 or p38, abrogated the ability of KGF to maintain the AT2 cell phenotype, as evidenced by loss of expression of lamellar membrane protein (p180) and increased reactivity with the AT1 cell-specific monoclonal antibody VIIIB2 by Day 6 in culture. Overexpression of JNKK2, upstream kinase of JNK, increased activation of endogenous c-Jun in association with increased expression of p180 and abrogation of AQP5, suggesting that activation of c-Jun promotes retention of the AT2 cell phenotype. These results indicate that retention of the AT2 cell phenotype by KGF involves c-Jun and suggest that activation of c-Jun kinase may be an important determinant of maintenance of AT2 cell phenotype.
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