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Title: Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor

Allergic contact dermatitis (ACD) is a cell-mediated immune response that involves skin sensitization in response to contact with various allergens. Angiogenesis and lymphangiogenesis both play roles in the allergic sensitization process. Epidermal keratinocytes can produce vascular endothelial growth factor (VEGF) in response to UV irradiation and during wound healing. However, the effect of haptenic chemical allergens on the VEGF production of human keratinocytes, which is the primary contact site of toxic allergens, has not been thoroughly researched. We systematically investigated whether immune-regulatory cytokines and chemical allergens would lead to the production of VEGF in normal human keratinocytes (NHKs) in culture. VEGF production significantly increased when NHKs were treated with IFNγ, IL-1α, IL-4, IL-6, IL-17A, IL-22 or TNFα. Among the human sensitizers listed in the OECD Test Guideline (TG) 429, we found that CMI/MI, DNCB, 4-phenylenediamine, cobalt chloride, 2-mercaptobenzothiazole, citral, HCA, cinnamic alcohol, imidazolidinyl urea and nickel chloride all significantly upregulated VEGF production in NHKs. In addition, common human haptenic allergens such as avobenzone, formaldehyde and urushiol, also induced the keratinocyte-derived VEGF production. VEGF upregulation by pro-inflammatory stimuli, IFNγ, DNCB or formaldehyde is preceded by the production of IL-8, an acute inflammatory phase cytokine. Lymphangiogenic VEGF-C gene transcription was significantly increasedmore » when NHKs were treated with formaldehyde, DNCB or urushiol, while transcription of VEGF-A and VEGF-B did not change. Therefore, the chemical allergen-induced VEGF upregulation is mainly due to the increase in lymphangiogenic VEGF-C transcription in NHKs. These results suggest that keratinocyte-derived VEGF may regulate the lymphangiogenic process during the skin sensitization process of ACD. - Highlights: • Pro-inflammatory cytokines induced VEGF production in normal human keratinocytes (NHKs). • Chemical allergens stimulate NHKs to produce VEGF. • VEGF production is preceded by IL-8 production in NHKs. • IFNγ, DNCB and formaldehyde increase lymphangiogenic VEGF-C gene transcription. • VEGF production in NHKs may be a biomarker for the prediction of potential contact allergens.« less
Authors:
 [1] ; ; ; ;  [2] ;  [1] ;  [3] ;  [4] ;  [5] ;  [2]
  1. College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791 (Korea, Republic of)
  2. College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742 (Korea, Republic of)
  3. College of Pharmacy, Yeungnam University, Gyeongsan 712-749 (Korea, Republic of)
  4. College of Pharmacy, Chung-Ang University, Seoul 156-756 (Korea, Republic of)
  5. Department of Dermatology, Dongguk University Ilsan Hospital, Goyang 410-773 (Korea, Republic of)
Publication Date:
OSTI Identifier:
22465710
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 283; Journal Issue: 2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALCOHOLS; ANGIOGENESIS; BIOLOGICAL MARKERS; COBALT CHLORIDES; DERMATITIS; FORMALDEHYDE; GENES; HEALING; HUMAN POPULATIONS; INFLAMMATION; LYMPHOKINES; NICKEL CHLORIDES; SENSITIZERS; SKIN; TOXICITY; TRANSCRIPTION; UREA; WOUNDS