FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis
Loka R. Penke, Jennifer M. Speth, Vijaya L. Dommeti, Eric S. White, Ingrid L. Bergin, Marc Peters-Golden
Loka R. Penke, Jennifer M. Speth, Vijaya L. Dommeti, Eric S. White, Ingrid L. Bergin, Marc Peters-Golden
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Research Article Pulmonology

FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

Abstract

While the transcription factor forkhead box M1 (FOXM1) is well known as a proto-oncogene, its potential role in lung fibroblast activation has never been explored. Here, we show that FOXM1 is more highly expressed in fibrotic than in normal lung fibroblasts in humans and mice. FOXM1 was required not only for cell proliferation in response to mitogens, but also for myofibroblast differentiation and apoptosis resistance elicited by TGF-β. The lipid mediator PGE2, acting via cAMP signaling, was identified as an endogenous negative regulator of FOXM1. Finally, genetic deletion of FOXM1 in fibroblasts or administration of the FOXM1 inhibitor Siomycin A in a therapeutic protocol attenuated bleomycin-induced pulmonary fibrosis. Our results identify FOXM1 as a driver of lung fibroblast activation and underscore the therapeutic potential of targeting FOXM1 for pulmonary fibrosis.

Authors

Loka R. Penke, Jennifer M. Speth, Vijaya L. Dommeti, Eric S. White, Ingrid L. Bergin, Marc Peters-Golden

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Figure 1

Fibrotic fibroblasts exhibit increased FOXM1 expression.

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Fibrotic fibroblasts exhibit increased FOXM1 expression. (A and B) Basal...
(A and B) Basal FOXM1 expression in fibroblasts grown from lungs of patients with IPF and control nonfibrotic lungs by qPCR analysis (A) and Western blot analysis (B). (C and D) Basal FOXM1 expression in fibroblasts grown from lungs of bleomycin- and saline-treated mice by qPCR analysis (C) and Western blot analysis (D). Each numeral in A and B denotes a single patient–derived cell line. In C, each symbol represents an individual murine-derived line of fibroblasts. Bars represent mean ± SEM. In B and D, each lane represents an individual patient- or murine-derived line of fibroblasts. *P < 0.05.