Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses.
Arsenic contamination of drinking water is a matter of global concern. Arsenic intake impairs immune responses and leads to a variety of pathological conditions including cancer. In order to understand the intricate tuning of immune responses elicited by chronic exposure to arsenic, a mouse model was established by subjecting mice to different environmentally relevant concentrations of arsenic in drinking water for 30days. Detailed study of the thymus, a primary immune organ, revealed arsenic-mediated tissue damage in both histological specimens and scanning electron micrographs. Analysis of molecular markers of apoptosis by Western blot revealed a dose-dependent activation of the apoptotic cascade. Enzymatic assays supported oxidative stress as an instigator of cell death. Interestingly, assessment of inflammatory responses revealed disparity in the NF-κB/IL-6/STAT3 axis, where it was found that in animals consuming higher amounts of arsenic NF-κB activation did not lead to the classical IL-6 upregulation response. This deviation from the canonical pathway was accompanied with a significant rise in numbers of CD4+ CD25+ FoxP3 expressing cells in the thymus. The cytokine profile of the animals exposed to higher doses of arsenic also indicated an immune-suppressed milieu, thus validating that arsenic shapes the immune environment in context to its dose of exposure and that at higher doses it leads to immune-suppression. Our study establishes a novel role of arsenic in regulating immune homeostasis in context to its dose, where, at higher doses, arsenic related upregulation of NF-κB cascade takes on an alternative role that is correlated with increased immune-suppression.
Department of Physiology, UCSTA, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India.
Sreetama
S
Choudhury
Department of Physiology, UCSTA, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India.
Payal
P
Gupta
Department of Physiology, UCSTA, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India.
Sayan
S
Ghosh
Department of Physiology, UCSTA, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India.
Sudeshna
S
Mukherjee
Department of Physiology, UCSTA, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India.
Priyanka
P
Chakraborty
Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India.
Urmi
U
Chatterji
Department of Physiology, UCSTA, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India. Electronic address: scphys@caluniv.ac.in.
Sreya
S
Chattopadhyay
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000008:administration & dosage / Q000633:toxicity*; D016207:Cytokines; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D060766:Drinking Water / Q000737:chemistry; D007107:Immune System / Q000187:drug effects; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D060168:Thymocytes / Q000187:drug effects* / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology; D014874:Water Pollutants, Chemical / Q000008:administration & dosage / Q000633:toxicity*
D016207:Cytokines; D060766:Drinking Water; D015850:Interleukin-6; D016328:NF-kappa B; D014874:Water Pollutants, Chemical; D001151:Arsenic
Apoptosis; Arsenic; NF-κB/IL-6/STAT3; Oxidative stress; Thymus; nTreg