Role of interferon-gamma in the evolution of murine bleomycin lung fibrosis.
IFN-gamma 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-gamma expression in bleomycin-induced lung injury. IFN-gamma mRNA in LC from bleomycin-treated mice peaked 3 days after intratracheal instillation. IFN-gamma protein levels were increased at 6 days, as was the percentage of LC expressing IFN-gamma. CD4+, CD8+, and natural killer cells each contributed significantly to IFN-gamma 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-gamma production by these cells. To define the role of endogenous IFN-gamma in the evolution of bleomycin lung injury, we compared the effect of bleomycin in mice with a targeted knockout mutation of the IFN-gamma gene (IFN-gamma knockout) and wild-type mice. At 14 days after intratracheal bleomycin, total bronchoalveolar lavage cell counts and lung hydroxyproline were decreased in IFN-gamma knockouts compared with wild-type animals. There was no difference in morphometric parameters of fibrosis. Our data show that enhanced IFN-gamma production in the lungs of bleomycin-treated mice is at least partly IL-12 and IL-18 dependent. Absence of IFN-gamma in IFN-gamma knockout mice does not increase pulmonary fibrosis. Endogenous IFN-gamma may play a proinflammatory or profibrotic role in bleomycin-induced lung fibrosis.
Segel
Michael J
MJ
Lung Cellular & Molecular Biology Laboratories, Institute of Pulmonology, Hadassah University Hospital, Jerusalem 91120, Israel.
Izbicki
Gabriel
G
Cohen
Pazit Y
PY
Or
Reuven
R
Christensen
Thomas G
TG
Wallach-Dayan
Shulamit B
SB
Breuer
Raphael
R
D000818:Animals; D000964:Antimetabolites, Antineoplastic; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D001761:Bleomycin; D007371:Interferon-gamma