title: Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor.
abstract: 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 increased 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.
authors.affiliation: College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791, Republic of Korea.
authors.forename: Ok-Nam
authors.initials: ON
authors.lastname: Bae
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Seyeon
authors.initials: S
authors.lastname: Ahn
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Jin
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791, Republic of Korea.
authors.forename: Eun-Sun
authors.initials: ES
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Tae Cheon
authors.initials: TC
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea.
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Chun
authors.affiliation: Department of Dermatology, Dongguk University Ilsan Hospital, Goyang 410-773, Republic of Korea. Electronic address: leeay@duih.org.
authors.forename: Ai-Young
authors.initials: AY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: minsoo@alum.mit.edu.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Noh
mesh_terms: D000485:Allergens / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D052816:Foreskin / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D042583:Lymphangiogenesis / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D000485:Allergens; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Allergic contact dermatitis (ACD); IL-8; Lymphangiogenesis; Normal human keratinocytes; OECD TG429; VEGF