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

Details

• Alternative Title:
  J Immunol
• Personal Author:
  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 J. ; Zeki, Amir A.
• Description:
  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 μM 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.
• Subjects:
  Animals Asthma Bronchi Bronchial Hyperreactivity Disease Models, Animal Enzyme Inhibitors Eosinophils Epithelial Cells Farnesyltranstransferase Humans Inflammation Lung Male Methionine Mice Mice, Inbred BALB C Ovalbumin Polyisoprenyl Phosphates Ras Proteins Sesquiterpenes Signal Transduction

  More +
• Keywords:
  Airway Hyperreactivity Airway Inflammation Asthma Eosinophils Farnesylation Farnesyl Diphosphate Farnesylpyrophosphate Farnesyltransferase Inhibition FTI-277 Isoprenylation Ras GTPase

  More +
• Source:
  J Immunol. 200(11):3840-3856
• Pubmed ID:
  29703864
• Pubmed Central ID:
  PMC5964018
• Document Type:
  Journal Article
• Funding:
  R01 HL105573/HL/NHLBI NIH HHSUnited States/ ; K08 HL114882/HL/NHLBI NIH HHSUnited States/ ; T32 HL007013/HL/NHLBI NIH HHSUnited States/ ; KL2 RR024144/RR/NCRR NIH HHSUnited States/ ; U54 OH007550/OH/NIOSH CDC HHSUnited States/ ; R01 HL066189/HL/NHLBI NIH HHSUnited States/ ; U54OH007550/ACL/ACL HHSUnited States/
• Volume:
  200
• Issue:
  11
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:f876b2d4d104b52aee76406bb8308567f58b4fb0c159a8750c9675a16e20e4c6
• Download URL:
  https://stacks.cdc.gov/view/cdc/55074/cdc_55074_DS1.pdf
• File Type:
  [PDF - 1.97 MB ]