Mast Cells Localize in Hypoxic Zones of Tumors and Secrete CCL-2 under Hypoxia through Activation of L-Type Calcium Channels.

Autor: Ramírez-Moreno IG; Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Tlalpan, 14330 Mexico City, Mexico., Ibarra-Sánchez A; Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Tlalpan, 14330 Mexico City, Mexico., Castillo-Arellano JI; Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 Mexico City, Mexico; and., Blank U; Inserm U1149, CNRS ERL 8252, Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site X. bichat, Laboratorie d'excellence INFLAMEX, 75018 Paris, France., González-Espinosa C; Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Tlalpan, 14330 Mexico City, Mexico; cgonzal@cinvestav.mx.
Jazyk: angličtina
Zdroj: Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2020 Feb 15; Vol. 204 (4), pp. 1056-1068. Date of Electronic Publication: 2020 Jan 03.
DOI: 10.4049/jimmunol.1801430
Abstrakt: Hypoxia is a condition that together with low pH, high amounts of reactive oxygen species (ROS), and increased adenosine levels characterize tumor microenvironment. Mast cells (MCs) are part of tumor microenvironment, but the effect of hypoxia on the production of MC-derived cytokines has not been fully described. Using the hypoxia marker pimonidazole in vivo, we found that MCs were largely located in the low-oxygen areas within B16-F1 mice melanoma tumors. In vitro, hypoxia promoted ROS production, a ROS-dependent increase of intracellular calcium, and the production of MCP 1 (CCL-2) in murine bone marrow-derived MCs. Hypoxia-induced CCL-2 production was sensitive to the antioxidant trolox and to nifedipine, a blocker of L-type voltage-dependent Ca 2+ channels (LVDCCs). Simultaneously with CCL-2 production, hypoxia caused the ROS-dependent glutathionylation and membrane translocation of the α1c subunit of Cav1.2 LVDCCs. Relationship between ROS production, calcium rise, and CCL-2 synthesis was also observed when cells were treated with H 2 O 2 In vivo, high CCL-2 production was detected on hypoxic zones of melanoma tumors (where tryptase-positive MCs were also found). Pimonidazole and CCL-2 positive staining diminished when B16-F1 cell-inoculated animals were treated with trolox, nifedipine, or the adenosine receptor 2A antagonist KW6002. Our results show that MCs are located preferentially in hypoxic zones of melanoma tumors, hypoxia-induced CCL-2 production in MCs requires calcium rise mediated by glutathionylation and membrane translocation of LVDCCs, and this mechanism of CCL-2 synthesis seems to operate in other cells inside melanoma tumors, with the participation of the adenosine receptor 2A.
(Copyright © 2020 by The American Association of Immunologists, Inc.)
Databáze: MEDLINE
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