α1-Antitrypsin (α1-AT) plays a key role in lung homeostasis. Although the hepatocyte is considered as the primary source of α1-AT, we have previously demonstrated that rat alveolar epithelial type II cells as well as the human A549 cell line synthesize α1-AT, suggesting its local production within the lung. In the present study, we showed that oncostatin M, as opposed to interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), or IL-6, is a potent stimulator of α1-AT synthesis in the human A549 cell line. The oncostatin M-induced α1-AT secretion is modulated by interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) at both the protein and mRNA levels. IFN-γ decreases oncostatin M-induced α1-AT secretion. By contrast, TGF-β in combination with oncostatin M induces a dramatic and synergistic upregulation that is not observed in the HepG2 hepatocyte cell line. Our results suggest that during an inflammatory process, alveolar epithelial cells may contribute to the antiprotease defense within the lung.