The present study was undertaken to elucidate the mechanism for the antifibrotic effect of interferon gamma (IFN-γ) in the bleomycin (BL)-mouse model of lung fibrosis. The expression of transforming growth factor (TGF-β) and procollagen I and III and their mRNAs was investigated in the BL-mouse model of lung fibrosis with and without IFN-γ treatment by Northern and slot blot analyses. Temporal changes in the content of procollagen and TGF-γ mRNAs in the lungs of mice receiving saline or BL by intratracheal route, with and without IFN-γ treatment by intramuscular route, were quantitated. The level of TGF-γ mRNA increased rapidly and peaked at day 5, whereas the levels of mRNAs for procollagens α₁(I) and α₁ (III) peaked at 10 days after BL instillation. The peak levels of these mRNAs in BL-treated animals were five- to sevenfold higher than those of the control. The increase in TGF-β mRNA in the lungs of BL-treated mice preceded the increase in the synthesis of type I and type III procollagen mRNAs. BL treatment also increased the hydroxyproline content significantly from 3 to 14 days as compared to the corresponding saline control groups. A maximal increase to 447 μg/lung from 223 [μ/lung in saline control was obtained at 10 days after instillation. Daily treatment with IFN-γ markedly reduced the BL-induced increases in the mRNA levels of TGF-β, and procollagen α (I) and α (III) without any effect on the lung level of β-actin mRNA. IFN-γy treatment also caused significant reduction in the BL-induced increase in the lung hydroxyproline content from 417 to 283 μ/lung at 7 days and from 447 to 264 μg/lung at 10 days. It may be concluded from the findings of the present study that the cellular mechanisms for the antifibrotic effect of IFN-y in the BL-mouse model of lung fibrosis are to initially downregulate the BL-induced overexpression of TGF-β mRNA, and subsequently procollagen mRNAs, leading to a decreased collagen content.