title: PDE4 inhibition suppresses IL-17-associated immunity in dry eye disease.
abstract: OBJECTIVE
  To determine the effect of phosphodiesterase type-4 (PDE4) inhibition on IL-17-associated immunity in experimental dry eye disease (DED).
  
  
  METHODS
  Murine DED was induced, after which a PDE4 inhibitor (cilomilast), dexamethasone, cyclosporine, or a relevant vehicle was administered topically. Real-time PCR, immunohistochemical staining, and flow cytometry were employed to evaluate the immuno-inflammatory parameters of DED with a focus on IL-17-associated immunity. Corneal fluorescein staining (CFS) was performed to evaluate clinical disease progression.
  
  
  RESULTS
  DED induction increased proinflammatory cytokine expression, pathogenic immune cell infiltration, and CFS scores. Cilomilast significantly decreased the expression of TNF-α in the cornea (P ≤ 0.05) and IL-1α, IL-1β, and TNF-α in the conjunctiva (P ≤ 0.05) as compared with vehicle control. Cilomilast treatment markedly decreased the presence of CD11b+ antigen-presenting cells in the central and peripheral cornea (P ≤ 0.05), and led to decreased conjunctival expression of cytokines IL-6, IL-23, and IL-17 (P ≤ 0.05). Moreover, cilomilast decreased the expression of IL-17 and IL-23 in the draining lymph nodes (P ≤ 0.05). Topical cilomilast was significantly more effective than vehicle at reducing CFS scores (P ≤ 0.05). The therapeutic efficacy of cilomilast was comparable or superior to that of dexamethasone and cyclosporine in all tested measures.
  
  
  CONCLUSIONS
  Topical cilomilast suppresses the generation of IL-17-associated immunity in experimental DED.
authors.affiliation: Schepens Eye Research Institute and Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Sadrai
authors.forename: William
authors.initials: W
authors.lastname: Stevenson
authors.forename: Andre
authors.initials: A
authors.lastname: Okanobo
authors.forename: Yihe
authors.initials: Y
authors.lastname: Chen
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Dohlman
authors.forename: Jing
authors.initials: J
authors.lastname: Hua
authors.forename: Francisco
authors.initials: F
authors.lastname: Amparo
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Chauhan
authors.forename: Reza
authors.initials: R
authors.lastname: Dana
mesh_terms: D000818:Animals; D003228:Conjunctiva / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003315:Cornea / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D015352:Dry Eye Syndromes / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D007113:Immunity, Innate / Q000187:drug effects*; D007150:Immunohistochemistry; D015851:Interleukin-7 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009570:Nitriles / Q000008:administration & dosage; D009883:Ophthalmic Solutions; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage*; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D003509:Cyclohexanecarboxylic Acids; D015851:Interleukin-7; D009570:Nitriles; D009883:Ophthalmic Solutions; D058988:Phosphodiesterase 4 Inhibitors; D012313:RNA; C433247:Cilomilast