Role of interferon-γ in the evolution of murine bleomycin lung fibrosis

IFN-γ production is upregulated in lung cells (LC) of bleomycin-treated C57BL/6 mice. The present study characterizes the time course, cellular source, and regulation of IFN-γ expression in bleomycin-induced lung injury. IFN-γ mRNA in LC from bleomycin-treated mice peaked 3 days after intratracheal instillation. IFN-γ protein levels were increased at 6 days, as was the percentage of LC expressing IFN-γ. CD4⁺, CD8⁺, and natural killer cells each contributed significantly to IFN-γ production. IL-12 mRNA levels were increased at 1 day in LC of bleomycin-treated mice. Anti-IL-12 and anti-IL-18 antibodies decreased IFN-γ production by these cells. To define the role of endogenous IFN-γ in the evolution of bleomycin lung injury, we compared the effect of bleomycin in mice with a targeted knockout mutation of the IFN-γ gene (IFN-γ knockout) and wild-type mice. At 14 days after intratracheal bleomycin, total bronchoalveolar lavage cell counts and lung hydroxyproline were decreased in IFN-γ knockouts compared with wild-type animals. There was no difference in morphometric parameters of fibrosis. Our data show that enhanced IFN-γ production in the lungs of bleomycin-treated mice is at least partly IL-12 and IL-18 dependent. Absence of IFN-γ in IFN-γ knockout mice does not increase pulmonary fibrosis. Endogenous IFN-γ may play a proinflammatory or profibrotic role in bleomycin-induced lung fibrosis.