Acute 4,4′-Methylene Diphenyl Diisocyanate Exposure-Mediated Downregulation of miR-206-3p and miR-381-3p Activates Inducible Nitric Oxide Synthase Transcription by Targeting Calcineurin/NFAT Signaling in Macrophages

Details

• Personal Author:
  Hettick JM ; Law, Brandon F. ; Lin C-C
• Description:
  Exposure to 4,4'-methylene diphenyl diisocyanate (MDI) in the occupational setting may lead to development of occupational asthma (OA), and the underlying molecular mechanisms of MDI-induced disease pathogenesis remain an active area of research. Using a nose-only mouse inhalation model, we find that circulating microRNA (miR)-206-3p and miR-381-3p are downregulated after MDI exposure; however, cellular miR-206-3p and miR-381-3p responses after MDI aerosol exposure and their pathophysiological roles in MDI-OA are unknown. We hypothesize that miR-206-3p and miR-381-3p-regulated mechanisms cause increased expression of the inducible nitric oxide synthase (iNOS) after MDI aerosol exposure. We examined cellular miR-206-3p and miR- 381-3p, calcineurins, nuclear factors of activated T-cells (NFATs) and iNOS levels from both nose-only exposed murine bronchoalveolar lavage cells (BALCs) and differentiated THP-1 macrophages treated with MDI-glutathione (GSH) conjugates. Both in vivo murine MDI aerosol exposure and in vitro MDI-GSH exposures in THP-1 macrophages results in downregulation of endogenous miR-206-3p and miR-381-3p and upregulation of PPP3CA and iNOS expression. Transfection of THP-1 macrophages with miR-inhibitor-206-3p and miR-inhibitor-381-3p resulted in the upregulation of PPP3CA and iNOS. Using RNA-induced silencing complex immunoprecipitation (RISC-IP) and translational reporter assays, we verified that PPP3CA, but not iNOS, is directly targeted by both miR-206-3p and miR-381-3p. Downregulation of miR-206-3p and miR-381-3p following by MDI exposure induces Calcineurin/NFAT signaling-mediated iNOS transcription in macrophages and BALCs. [Description provided by NIOSH]
• Subjects:
  Aerosols Asthma, Occupational Blood Enzymes Isocyanates Laboratories Macrophages Occupational Health Respiratory System Safety
• Keywords:
  4,4'-methylene Diphenyl Diisocyanate 4,4'methylenebisphenyl Isocyanate Author Keywords: Occupational Asthma Calcineurin/NFAT Signaling Cell Signaling Diisocyanates DNCOs Enzyme Activity Inhalation Studies INOS Laboratory Animals MDI OA Occupational Asthma Pathogenesis PPP3CA

  More +
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  100-113
• Volume:
  173
• Issue:
  1
• NIOSHTIC Number:
  nn:20057640
• Citation:
  Toxicol Sci 2020 Jan; 173(1):100-113
• Contact Point Address:
  Chen-Chung Lin, NIOSH/HELD/ACIB, 1095 Willowdale Rd., MS L4020, Morgantown, WV 26505
• Email:
  mjy2@cdc.gov
• CAS Registry Number:
  Diphenylmethane diisocyanate (CAS RN 101-68-8)
• Federal Fiscal Year:
  2020
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Toxicological Sciences
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:096ebd7b0d9cad79afe66cf2323590f6bc50559abf0885818119f0567b1c4358c574a8ff4eb6fa00450421e4e92ca1cb9dddf11490d58acdd2e648bf5faef974
• Download URL:
  https://stacks.cdc.gov/view/cdc/214912/cdc_214912_DS1.pdf
• File Type:
  [PDF - 892.17 KB ]