title: Phenylbutyrate suppresses distinct skin reactions that are enhanced by blockade of epidermal growth factor receptor signaling.
abstract: BACKGROUND
  Epidermal growth factor receptor inhibitors (EGFRIs) cause skin inflammation, and understanding the factors that mediate this reaction is fundamental for designing therapies for EGFRI-related cutaneous side effects.
  
  
  OBJECTIVE
  We characterized EGFRI-enhanced skin reactions and evaluated the therapeutic efficacy of phenylbutyrate, a histone deacetylase inhibitor.
  
  
  METHODS
  PD168393, an EGFRI, was applied topically to the ear skin of mice with or without mast cell deficiency. The skin was then irritated once or pre-sensitized and repeatedly challenged with 2,4-dinitrofluorobenzene (DNFB). The reaction pattern, the type and number of infiltrating cells, changes in protein, cytokine (TNF-α) and chemokine (CCL2) expression, and the immune response were analyzed. Phenylbutyrate, formulated as a gel for topical treatment or dissolved in water for intraperitoneal administration, was tested as a treatment.
  
  
  RESULTS
  EGFRI rapidly upregulated the mast cell chemotactic factor, stem cell factor (SCF) and augmented DNFB-induced immediate contact dermatitis within hours of treatment in the presence of mast cells. Topical phenylbutyrate treatment suppressed EGFRI-induced SCF expression in the epithelium, inhibited DNFB-induced mast cell recruitment in the dermis, and ameliorated the EGFRI-enhanced acute skin reaction. EGFRI also enhanced the delayed-type DNFB-induced hypersensitive reaction that was mast-cell independent but was associated with T lymphocytes. Systemic phenylbutyrate administration suppressed EGFRI-enhanced delayed-type skin hypersensitivity by increasing the number and function of Foxp3(+) T regulatory suppressor cells, which inhibited T helper cell proliferation.
  
  
  CONCLUSIONS
  Our data suggest that phenylbutyrate has dual beneficial therapeutic effects on EGFRI-enhanced acute (local inflammatory) and late (systemic immune) skin reactions.
authors.affiliation: Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan. ylchung@kfsyscc.org
authors.forename: Yih-Lin
authors.initials: YL
authors.lastname: Chung
authors.forename: Newman N M
authors.initials: NN
authors.lastname: Pui
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D017449:Dermatitis, Allergic Contact / Q000201:enzymology / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004139:Dinitrofluorobenzene; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011799:Quinazolines / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D019089:Stem Cell Factor / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D056572:Histone Deacetylase Inhibitors; D007166:Immunosuppressive Agents; C509204:PD168393; D010654:Phenylbutyrates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha; D004139:Dinitrofluorobenzene; C541485:EGFR protein, mouse; D066246:ErbB Receptors