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

Abstract

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.

Activated T killer cells induce apoptosis in lung epithelial cells and the release of pro‐inflammatory cytokine TNF‐α

“…We then asked whether epithelial cells could be destroyed by the CTL and undergo apoptosis. Since increased IFN-+ production had previously been found in the lungs of patients with asbestosis [30] and in the lungs of animal models of bacterial superantigen-induced pneumonitis [31] and bleomycin-induced pneumonitis [32], epithelial cells were employed that were either treated or untreated with IFN-+ . We showed that SEBstimulated human CD8 + CTL induced apoptosis in the human lung epithelial cell line A549 primarily through the perforin/granzyme pathway.…”

“…Since increased IFN-+ production has previously been detected in the lungs of patients with asbestosis [30] and in the lungs of animal models of interstitial pneumonia [31,32], we asked whether resistance to apoptosis mediated by ligands such as CD95L, TRAIL, or TNF- § could be modified by IFN-+ . Thus, we determined whether triggering of CD95, TRAIL-R, and TNFR in the absence or presence of IFN-+ induces apoptosis of A549 cells in order to evaluate the roles of death pathways from these receptors in CD8 CTL-mediated A549 cell death in an interferoncontaining environment.…”

TLR2-Mediated Production of IL-27 and Chemokines by Respiratory Epithelial Cells Promotes Bleomycin-Induced Pulmonary Fibrosis in Mice

“…During pulmonary fibrosis, various immune cells infiltrate the lung tissues, which have a complicated cytokine network that regulates inflammation and fibrosis (3). Th1-type cytokines, such as IFN-g, prevent fibroblast activation and pulmonary fibrosis (4,5), whereas Th2-type cytokines, such as IL-4 and IL-13, promote these processes (6,7). Mice deficient in myeloid differentiation factor 88 (MyD88), an adaptor protein in the signal transduction pathway mediated by IL-1 and TLRs, exhibit a profound defect in the activation of Ag-specific Th1 immune responses, but not in Th2 immune responses, suggesting that TLR signaling has a critical role in balancing Th1/Th2 responses (8).…”

E- and P-Selectins Synergistically Inhibit Bleomycin-Induced Pulmonary Fibrosis

“…31,32 By contrast, other studies have shown that IFN-␥ production is increased in bleomycin-induced pulmonary fibrosis, suggesting a pathogenic role for IFN-␥. 21,33 Furthermore, bleomycin-induced lung fibrosis was attenuated in IFN-␥-deficient mice. 21 Results of this study showed that lack of E-selectin, with or without P-selectin blockade, reduced IFN-␥ expression and augmented lung fibrosis, suggesting a protective effect of IFN-␥.…”

“…21,33 Furthermore, bleomycin-induced lung fibrosis was attenuated in IFN-␥-deficient mice. 21 Results of this study showed that lack of E-selectin, with or without P-selectin blockade, reduced IFN-␥ expression and augmented lung fibrosis, suggesting a protective effect of IFN-␥. However, exogenous IFN-␥ treatment did not affect the severity of lung fibrosis or mortality rate in E-selectin Ϫ/Ϫ mice (data not shown), although Jiang and colleagues 32 have demonstrated that treatment with exogenous IFN-␥ in CXCR3 Ϫ/Ϫ mice could reverse the fibrotic phenotype and significantly attenuate the development of lung fibrosis.…”