ONCOSTATIN-M, BUT NOT INTERLEUKIN-6 OR LEUKEMIA INHIBITORY FACTOR, STIMULATES EXPRESSION OF ALPHA(1)-PROTEINASE INHIBITOR IN A549 HUMAN ALVEOLAR EPITHELIAL-CELLS

Alpha-1 proteinase inhibitor (A1-Pi) is the main serine proteinase inh ibitor found in human plasma and is a potent elastase inhibitor in var ious tissues, including lung, Al-Pi is expressed and induced in liver during inflammatory responses but can also be produced by epithelial c ells, Since hepatocyte Al-Pi production is stimulated by interleukin-6 (IL-6) and other gp130-cytokines, such as leukemia inhibitory factor (LIF) and oncostatin M (OM), we investigated the role of these cytokin es in regulating Al-pi in lung epithelial cells, We show that OM, a mo nocyte and T cell product, can specifically and potently induce A1-Pi production in lung-derived A549 alveolar (epithelial) cells, as web as in liver-derived HepG2 cells, Both Al-Pi protein (as detected by ELIS A and Western blots) and mRNA levels were enhanced 20-fold to 30-fold in A549 cells, OM was also able to stimulate the expression of tissue inhibitor of metalloproteinase-1 in these cells, Interestingly, other members of the IL-6 family (IL-6 and LIF) had little or no effect on A 549 cells, and proinflammatory cytokines, such as IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) also had no stimulatory effect on A1 -Pi synthesis in A549 cells, Costimulation with IL-1 beta resulted in a decrease in AI-Pi production from OM-stimulated A549 cells, However, IL-6 production was synergistically enhanced, OM was also able to sti mulate A1-Pi production from a bronchial epithelial primary cell line, whereas an intestinal epithelial cell line HT29 responded to IL-6 but not OM, These results suggest that lung levels Al-Pi could be derived not only from liver and inflammatory cells but also from epithelial c ells, which can be upregulated on stimulation by OM, This may have imp lications for regulation of local activity of human neutrophil elastas e (HNE) in such diseases as emphysema and cystic fibrosis.