Abstract
Fibroblast growth factors (FGFs) play key roles in the pathogenesis of different human diseases, but the cross‐talk between FGFs and other cytokines remains largely unexplored. We identified an unexpected antagonistic effect of FGFs on the interferon (IFN) signaling pathway. Genetic or pharmacological inhibition of FGF receptor signaling in keratinocytes promoted the expression of interferon‐stimulated genes (ISG) and proteins in vitro and in vivo. Conversely, FGF7 or FGF10 treatment of keratinocytes suppressed ISG expression under homeostatic conditions and in response to IFN or poly(I:C) treatment. FGF‐mediated ISG suppression was independent of IFN receptors, occurred at the transcriptional level, and required FGF receptor kinase and proteasomal activity. It is not restricted to keratinocytes and functionally relevant, since FGFs promoted the replication of herpes simplex virus I (HSV‐1), lymphocytic choriomeningitis virus, and Zika virus. Most importantly, inhibition of FGFR signaling blocked HSV‐1 replication in cultured human keratinocytes and in mice. These results suggest the use of FGFR kinase inhibitors for the treatment of viral infections.
Highlights
Fibroblast growth factors (FGFs) play key roles in the pathogenesis of different human diseases, but the cross-talk between FGFs and other cytokines remains largely unexplored
Upregulation of interferonstimulated genes (ISG) was confirmed by qRT–PCR analysis of epidermal RNA from adult mice for some of the genes identified in the microarray and for additional ISGs, including IFN response factor 7 (Irf7), radical S-adenosyl methionine domain containing 2 (Rsad2), 20-50-oligoadenylate synthetase-like 2 (Oasl2), IFN-induced protein with tetratricopeptide repeat 1 (Ifit1), signal transducer and activator of transcription 1 (Stat1), and Stat2 (Fig 1A)
FGFs exert their early effect on ISG expression at the transcriptional level and in an FGF receptor (FGFR) kinase-dependent, but IFN receptor-independent manner
Summary
Fibroblast growth factors (FGFs) play key roles in the pathogenesis of different human diseases, but the cross-talk between FGFs and other cytokines remains largely unexplored. Genetic or pharmacological inhibition of FGF receptor signaling in keratinocytes promoted the expression of interferonstimulated genes (ISG) and proteins in vitro and in vivo. FGF7 or FGF10 treatment of keratinocytes suppressed ISG expression under homeostatic conditions and in response to IFN or poly(I:C) treatment. FGF-mediated ISG suppression was independent of IFN receptors, occurred at the transcriptional level, and required FGF receptor kinase and proteasomal activity. It is not restricted to keratinocytes and functionally relevant, since FGFs promoted the replication of herpes simplex virus I (HSV-1), lymphocytic choriomeningitis virus, and Zika virus. Inhibition of FGFR signaling blocked HSV-1 replication in cultured human keratinocytes and in mice. These results suggest the use of FGFR kinase inhibitors for the treatment of viral infections
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