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 EGFR ligands and initiates EGFR/MEK/ERK signaling to downregulate tropoelastin mRNA in neonatal rat lung fibroblasts [DiCamillo et al. J Biol Chem 277: 18938-18946, 2002]. Here, we 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--like polypeptides, and requires EGFR/MEK/ERK signaling, as 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- signaling since TGF- type I receptor kinase inhibitor or TGF- 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- neutralizing antibody, EGF, TGF- or NE. Tropoelastin mRNA destabilization by NE, EGF or TGF- 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- 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--induced elastogenesis/elastin repair in the chronically inflamed, elastase-antielastase imbalanced lung in emphysema.