Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1

Abstract

Studies using genetically modified mice have revealed fundamental functions of the transcription factor Fos/AP-1 in bone biology, inflammation, and cancer. However, the biological role of the Fos-related protein Fra-2 is not well defined in vivo. Here we report an unexpected profibrogenic function of Fra-2 in transgenic mice, in which ectopic expression of Fra-2 in various organs resulted in generalized fibrosis with predominant manifestation in the lung. The pulmonary phenotype was characterized by vascular remodeling and obliteration of pulmonary arteries, which coincided with expression of osteopontin, an AP-1 target gene involved in vascular remodeling and fibrogenesis. These alterations were followed by inflammation; release of profibrogenic factors, such as IL-4, insulin-like growth factor 1, and CXCL5; progressive fibrosis; and premature mortality. Genetic experiments and bone marrow reconstitutions suggested that fibrosis developed independently of B and T cells and was not mediated by autoimmunity despite the marked inflammation observed in transgenic lungs. Importantly, strong expression of Fra-2 was also observed in human samples of idiopathic and autoimmune-mediated pulmonary fibrosis. These findings indicate that Fra-2 expression is sufficient to cause pulmonary fibrosis in mice, possibly by linking vascular remodeling and fibrogenesis, and suggest that Fra-2 has to be considered a contributing pathogenic factor of pulmonary fibrosis in humans.fra-2 transgenic mouse ͉ idiopathic pulmonary fibrosis ͉ osteopontin ͉ pulmonary arterial hypertension ͉ fibrosis mouse model

Loss of JUNB/AP-1 promotes invasive prostate cancer

“…23,24 Consistent with the increased invasiveness, Spp1 mRNA was increased in JunB ΔP ; Pten ΔP tumours (Figure 4d). Interestingly, IHC analyses indicated that SPP1 was increased in invasive and noninvasive double-mutant tumours mainly in the stroma (Figure 4e).…”

FOSL2 promotes leptin gene expression in human and mouse adipocytes

“…The generation of the heterozygous Fosl2 +/− , Fosl2 fl/fl , and Fosl2-tg mice has been reported previously (33,34). For the latter, Fosl2 was expressed under the control of the ubiquitous major histocompatibility complex class I antigen H-2K b promoter.…”

“…We wished to extend these gain-of-function experiments to an in vivo context, but global Fosl2-transgenic mice (Fosl2-tg) experience systemic fibrosis and inflammation, rendering them unsuitable for metabolic study (34). However, calvarial cells isolated from these mice showed elevated Lep expression compared with WT cells; this effect was apparent even before differentiation and reached significance at day 10 ( Figure 8B).…”

Gefitinib, but Not Erlotinib, is a Possible Inducer of Fra-1-mediated Interstitial Lung Disease

“…Ectopic transgenic expression of Fosl2 in various organs reportedly promotes generalized fibrosis, especially in the lung. 18 Therefore we investigated whether other Fos family genes, such as Fos or Fosl2, were induced by gefitinib, erlotinib or AG1517 treatment. None of the three EGFR inhibitors tested induced Fos or Fosl2 in macrophages in the presence or absence of LPS stimulation (Fig.…”