Farnesyltransferase inhibition exacerbates eosinophilic inflammation and airway hyperreactivity in mice with experimental asthma: The complex roles of ras GTPase and farnesylpyrophosphate in type 2 allergic inflammation

Jennifer M. Bratt, Kevin Y. Chang, Michelle Rabowsky, Lisa M. Franzi, Sean P. Ott, Simone Filosto, Tzipora Goldkorn, Muhammad Arif, Jerold A Last, Nicholas Kenyon, Amir Zeki

Research output: Contribution to journalArticle

Abstract

Ras, a small GTPase protein, is thought to mediate Th2-dependent eosinophilic inflammation in asthma. Ras requires cell membrane association for its biological activity, and this requires the posttranslational modification of Ras with an isoprenyl group by farnesyltransferase (FTase) or geranylgeranyltransferase (GGTase). We hypothesized that inhibition of FTase using FTase inhibitor (FTI)–277 would attenuate allergic asthma by depleting membrane-associated Ras. We used the OVA mouse model of allergic inflammation and human airway epithelial (HBE1) cells to determine the role of FTase in inflammatory cell recruitment. BALB/c mice were first sensitized then exposed to 1% OVA aerosol or filtered air, and half were injected daily with FTI-277 (20 mg/kg per day). Treatment of mice with FTI-277 had no significant effect on lung membrane–anchored Ras, Ras protein levels, or Ras GTPase activity. In OVA-exposed mice, FTI-277 treatment increased eosinophilic inflammation, goblet cell hyperplasia, and airway hyperreactivity. Human bronchial epithelial (HBE1) cells were pretreated with 5, 10, or 20 mM FTI-277 prior to and during 12 h IL-13 (20 ng/ml) stimulation. In HBE1 cells, FTase inhibition with FTI-277 had no significant effect on IL-13–induced STAT6 phosphorylation, eotaxin-3 peptide secretion, or Ras translocation. However, addition of exogenous FPP unexpectedly augmented IL-13–induced STAT6 phosphorylation and eotaxin-3 secretion from HBE1 cells without affecting Ras translocation. Pharmacological inhibition of FTase exacerbates allergic asthma, suggesting a protective role for FTase or possibly Ras farnesylation. FPP synergistically augments epithelial eotaxin-3 secretion, indicating a novel Ras-independent farnesylation mechanism or direct FPP effect that promotes epithelial eotaxin-3 production in allergic asthma. The Journal of Immunology, 2018, 200: 3840–3856.

Original languageEnglish (US)
Pages (from-to)3840-3856
Number of pages17
JournalJournal of Immunology
Volume200
Issue number11
DOIs
StatePublished - Jun 1 2018

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Farnesyltranstransferase
ras Proteins
Asthma
Inflammation
Prenylation
Epithelial Cells
Phosphorylation
Goblet Cells
Monomeric GTP-Binding Proteins
Interleukin-13
Post Translational Protein Processing
farnesyl pyrophosphate
Allergy and Immunology
Aerosols
Hyperplasia
Air
Cell Membrane
Pharmacology
Lung
Peptides

ASJC Scopus subject areas

  • Immunology

Cite this

Farnesyltransferase inhibition exacerbates eosinophilic inflammation and airway hyperreactivity in mice with experimental asthma : The complex roles of ras GTPase and farnesylpyrophosphate in type 2 allergic inflammation. / Bratt, Jennifer M.; Chang, Kevin Y.; Rabowsky, Michelle; Franzi, Lisa M.; Ott, Sean P.; Filosto, Simone; Goldkorn, Tzipora; Arif, Muhammad; Last, Jerold A; Kenyon, Nicholas; Zeki, Amir.

In: Journal of Immunology, Vol. 200, No. 11, 01.06.2018, p. 3840-3856.

Research output: Contribution to journalArticle

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abstract = "Ras, a small GTPase protein, is thought to mediate Th2-dependent eosinophilic inflammation in asthma. Ras requires cell membrane association for its biological activity, and this requires the posttranslational modification of Ras with an isoprenyl group by farnesyltransferase (FTase) or geranylgeranyltransferase (GGTase). We hypothesized that inhibition of FTase using FTase inhibitor (FTI)–277 would attenuate allergic asthma by depleting membrane-associated Ras. We used the OVA mouse model of allergic inflammation and human airway epithelial (HBE1) cells to determine the role of FTase in inflammatory cell recruitment. BALB/c mice were first sensitized then exposed to 1{\%} OVA aerosol or filtered air, and half were injected daily with FTI-277 (20 mg/kg per day). Treatment of mice with FTI-277 had no significant effect on lung membrane–anchored Ras, Ras protein levels, or Ras GTPase activity. In OVA-exposed mice, FTI-277 treatment increased eosinophilic inflammation, goblet cell hyperplasia, and airway hyperreactivity. Human bronchial epithelial (HBE1) cells were pretreated with 5, 10, or 20 mM FTI-277 prior to and during 12 h IL-13 (20 ng/ml) stimulation. In HBE1 cells, FTase inhibition with FTI-277 had no significant effect on IL-13–induced STAT6 phosphorylation, eotaxin-3 peptide secretion, or Ras translocation. However, addition of exogenous FPP unexpectedly augmented IL-13–induced STAT6 phosphorylation and eotaxin-3 secretion from HBE1 cells without affecting Ras translocation. Pharmacological inhibition of FTase exacerbates allergic asthma, suggesting a protective role for FTase or possibly Ras farnesylation. FPP synergistically augments epithelial eotaxin-3 secretion, indicating a novel Ras-independent farnesylation mechanism or direct FPP effect that promotes epithelial eotaxin-3 production in allergic asthma. The Journal of Immunology, 2018, 200: 3840–3856.",
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AU - Chang, Kevin Y.

AU - Rabowsky, Michelle

AU - Franzi, Lisa M.

AU - Ott, Sean P.

AU - Filosto, Simone

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