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Am J Physiol Lung Cell Mol Physiol 291: L232-L243, 2006. First published February 10, 2006; doi:10.1152/ajplung.00530.2005
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Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-beta on tropoelastin mRNA in lung fibroblasts

Sandra J. DiCamillo,1,* Shenghong Yang,1,* Maria V. Panchenko,2 Paul A. Toselli,1 Estee F. Naggar,1 Celeste B. Rich,1 Phillip J. Stone,1 Matthew A. Nugent,1 and Mikhail P. Panchenko1

Departments of 1Biochemistry and 2Medicine, Boston University School of Medicine, Boston, Massachusetts

Submitted 19 December 2005 ; accepted in final form 8 February 2006

Neutrophil elastase (NE) plays an important role in emphysema, a pulmonary disease associated with excessive elastolysis and ineffective repair of interstitial elastin. Besides its direct elastolytic activity, NE releases soluble epidermal growth factor receptor (EGFR) ligands and initiates EGFR/MEK/ERK signaling to downregulate tropoelastin mRNA in neonatal rat lung fibroblasts (DiCamillo SJ, Carreras I, Panchenko MV, Stone PJ, Nugent MA, Foster JA, and Panchenko MP. J Biol Chem 277: 18938–18946, 2002). We now report that NE downregulates tropoelastin mRNA in the rat fetal lung fibroblast line RFL-6. The tropoelastin mRNA downregulation is preceded by release of EGF-like and TGF-{alpha}-like polypeptides and requires EGFR/MEK/ERK signaling, because it is prevented by the EGFR inhibitor AG1478 and the MEK/ERK uncoupler U0126. Tropoelastin expression in RFL-6 fibroblasts is governed by autocrine TGF-beta signaling, because TGF-beta type I receptor kinase inhibitor or TGF-beta neutralizing antibody dramatically decreases tropoelastin mRNA and protein levels. Half-life of tropoelastin mRNA in RFL-6 cells is >24 h, but it is decreased to ~8 h by addition of TGF-beta neutralizing antibody, EGF, TGF-{alpha}, or NE. Tropoelastin mRNA destabilization by NE, EGF, or TGF-{alpha} is abolished by AG1478 or U0126. EGF-dependent tropoelastin mRNA downregulation is reversed upon ligand withdrawal, whereas chronic EGF treatment leads to persistent downregulation of tropoelastin mRNA and protein levels and decreases insoluble elastin deposition. We conclude that NE-initiated EGFR/MEK/ERK signaling cascade overrides the autocrine TGF-beta signaling on tropoelastin mRNA stability and, therefore, decreases the elastogenic response in RFL-6 fibroblasts. We hypothesize that persistent EGFR/MEK/ERK signaling could impede the TGF-beta-induced elastogenesis/elastin repair in the chronically inflamed, elastase/anti-elastase imbalanced lung in emphysema.

epidermal growth factor receptor; mitogen-activated protein kinase kinase; extracellular signal-regulated kinases 1 and 2; transforming growth factor-beta; elastin


Address for reprint requests and other correspondence: M. P. Panchenko, Dept. of Biochemistry, Boston Univ. School of Medicine, 715 Albany St., Boston, MA 02118 (e-mail: panchenko{at}biochem.bumc.bu.edu)




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