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

• Published in: Toxicology and applied pharmacology 2015-03, Vol.283 (2), p.147-155
• Main Authors: Bae, Ok-Nam, Ahn, Seyeon, Jin, Sun Hee, Hong, Soo Hyun, Lee, Jinyoung, Kim, Eun-Sun, Jeong, Tae Cheon, Chun, Young-Jin, Lee, Ai-Young, Noh, Minsoo
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ALCOHOLS; Allergens - pharmacology; Allergic contact dermatitis (ACD); ANGIOGENESIS; Animals; BIOLOGICAL MARKERS; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; COBALT CHLORIDES; DERMATITIS; Dose-Response Relationship, Drug; Epidermis - drug effects; Epidermis - immunology; Epidermis - metabolism; Foreskin - drug effects; Foreskin - immunology; Foreskin - metabolism; FORMALDEHYDE; GENES; HEALING; HUMAN POPULATIONS; Humans; IL-8; INFLAMMATION; Keratinocytes - drug effects; Keratinocytes - immunology; Keratinocytes - metabolism; Lymphangiogenesis; Lymphangiogenesis - drug effects; Lymphangiogenesis - physiology; LYMPHOKINES; Male; Mice; NICKEL CHLORIDES; Normal human keratinocytes; OECD TG429; SENSITIZERS; SKIN; TOXICITY; TRANSCRIPTION; UREA; Vascular Endothelial Growth Factor A - biosynthesis; VEGF; WOUNDS
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.01.008

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. [Display omitted] •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.