Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease characterized by hyperproliferation of type II epithelial cells in the interstitial space. IPF is thought to result from epithelial cell injury followed by aberrant wound healing and excessive accumulation of collagen, which lead to the development of fibroblastic foci or lesions. Interleukin (IL)-4, endothelin (ET)-1, and transforming growth factor beta (TGF-β) all induce transcriptional up-regulation of type I collagen, suggesting that all could enhance the accumulation of extracellular matrix (ECM) during the development of IPF. Interferon gamma-1b (IFN-γ 1b) has demonstrated anti-infective properties and is currently indicated for use in chronic granulomatous disease and malignant osteopetrosis. It is also under clinical study for the treatment of IPF, for which it may offer a survival benefit (Raghu G, Brown KK, Bradford WZ, et al. N Engl J Med. 2004;350(2):125-133).
To evaluate the effect of IFN-γ 1b on type I collagen synthesis, we studied its effect on IL-4, ET-1, and TGF-β–-induced type I collagen synthesis in human lung fibroblasts. Secreted collagen levels were determined by the ratio of total and collagenase-stable 3H-labeled protein in cell culture supernatants.
Relative to untreated cells, 5 ng/mL IL-4, ET-1, or TGF-β induced the expression of type I collagen by 42%, 58%, and 78%, respectively (p < 0.05). The collagen-inducing activities of IL-4, ET-1, and TGF-β were additive; collagen secretion increased 2.2-fold when cells were stimulated with all three (p < 0.05). A 5 ng/mL IFN-γ 1b dose reduced ET-1 and IL-4–stimulated collagen production to a level at or below that observed without stimulation; TGF-β–induced collagen secretion was decreased by 17% (p < 0.05). IFN-γ 1b was also effective in reducing collagen production from cells treated with any combination of IL-4, ET-1, and TGF-β. In cells treated with all three, IFN-γ 1b reduced collagen secretion by 18% (p < 0.05).
These results indicate that IFN-γ 1b may modulate fibrotic microenvironments that are associated with pathogenesis in IPF.
Our results support ongoing clinical research.
Osman Ozes, Shareholder; Employee All authors are employees of InterMune, Inc.; Product/procedure/technique that is considered research and is not yet approved for any purpose.