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Effects of KGF on Alveolar Epithelial Cell Transdifferentiation Are Mediated by JNK Signaling

¹ Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and Critical Care Medicine, ³ Department of Molecular Pharmacology and Toxicology; and ⁴ Institute for Genetic Medicine, Microarray Center, University of Southern California; and ² Bioinformatics User Facility, UCLA, Los Angeles, California

Correspondence and requests for reprints should be addressed to Renli Qiao, M.D., Division of Pulmonary and Critical Care Medicine, University of Southern California, 2020 Zonal Avenue, HMR911, Los Angeles, CA 90033. E-mail: rqiao{at}usc.edu

Rat alveolar epithelial cells (AEC) in primary culture transdifferentiate from a type II (AT2) toward 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 up-regulation 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 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 hours. Exposure to KGF activated all three MAPK, JNK, ERK1/2, and p38. 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.

Key Words: alveolar epithelium • mitogen-activated protein kinase • c-Jun • keratinocyte growth factor • microarray

CLINICAL RELEVANCE This article reports the novel finding that the effect of keratinocyte growth factor to reverse alveolar epithelial phenotype change is c-Jun N-terminal kinase–dependent. Thus the work links a specific signal transduction pathway to the phenotypic change in these cells.