title: STAT3-dependent VEGF production from keratinocytes abrogates dendritic cell activation and migration by arsenic: a plausible regional mechanism of immunosuppression in arsenical cancers.
abstract: Arsenic remains an important environmental hazard that causes several human cancers. Arsenic-induced Bowen's disease (As-BD), a skin carcinoma in situ, is the most common arsenical cancer. While great strides have been made in our understanding of arsenic carcinogenesis, how host immunity contributes to this process remains unknown. Patients with As-BD have an impaired contact hypersensitivity response. Although impaired T cell activation has been well-documented in arsenical cancers, how dendritic cell (DC), the key cell regulating innate immunity, regulates the immune response in arsenical cancers remains unclear. Using myeloid derived DC (MDDC) from patients with As-BD and normal controls as well as bone marrow derived DC (BMDC) from mice fed with or without arsenic, we measured the migration of DC. As-BD patients showed an impaired CCL21-mediated MDDC migration in vitro. Arsenic-fed mice had defective DC migration toward popliteal lymph nodes when injected with allogenic BMDCs via foot pad. Using skin from As-BD and normal controls, we found an increased expression of STAT3, a transcriptional factor contributing to impaired DC activation. Arsenic induced STAT3 activation and the production of VEGF in keratinocytes. The increase in VEGF was blocked by inhibiting STAT3 with RNA interference or pharmaceutically with JSI-124. While VEGF by itself minimally induced the expression of CD86 and MHC-II in MDDC, arsenic induced-MDDC activation was abolished by VEGF pretreatment. We concluded that the STAT3-VEGF axis in keratinocytes inhibits DC migration in the microenvironment of As-BD, indicating that cellular interactions play an important role in regulating the disease course of arsenical cancers.
authors.affiliation: Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Dermatology and Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chien-Hui
authors.initials: CH
authors.lastname: Hong
authors.affiliation: Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Dermatology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Gwo-Shing
authors.initials: GS
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Kee-Lung
authors.initials: KL
authors.lastname: Chang
authors.affiliation: National Environmental Toxicology Center, National Health Research Institutes, Zhunan, Taiwan; Department of Dermatology, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: dermyu@nhri.org.tw.
authors.forename: Hsin-Su
authors.initials: HS
authors.lastname: Yu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D020261:Arsenic Poisoning; D001854:Bone Marrow Cells / Q000166:cytology; D001913:Bowen's Disease / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D022423:Myeloid Cells / Q000166:cytology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D054421:Chemokine CCL21; D050796:STAT3 Transcription Factor; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; D001151:Arsenic; C038106:cucurbitacin I
keywords: Arsenic; Bowen’s disease; Dendritic cells; Keratinocytes; STAT3; VEGF