title: The Orai-1 and STIM-1 complex controls human dendritic cell maturation.
abstract: Ca(2+) signaling plays an important role in the function of dendritic cells (DC), the professional antigen presenting cells. Here, we described the role of Calcium released activated (CRAC) channels in the maturation and cytokine secretion of human DC. Recent works identified STIM1 and Orai1 in human T lymphocytes as essential for CRAC channel activation. We investigated Ca(2+) signaling in human DC maturation by imaging intracellular calcium signaling and pharmalogical inhibitors. The DC response to inflammatory mediators or PAMPs (Pathogen-associated molecular patterns) is due to a depletion of intracellular Ca(2+) stores that results in a store-operated Ca(2+) entry (SOCE). This Ca(2+) influx was inhibited by 2-APB and exhibited a Ca(2+)permeability similar to the CRAC (Calcium-Released Activated Calcium), found in T lymphocytes. Depending on the PAMPs used, SOCE profiles and amplitudes appeared different, suggesting the involvement of different CRAC channels. Using siRNAi, we identified the STIM1 and Orai1 protein complex as one of the main pathways for Ca(2+) entry for LPS- and TNF-α-induced maturation in DC. Cytokine secretions also seemed to be SOCE-dependent with profile differences depending on the maturating agents since IL-12 and IL10 secretions appeared highly sensitive to 2-APB whereas IFN-γ was less affected. Altogether, these results clearly demonstrate that human DC maturation and cytokine secretions depend on SOCE signaling involving STIM1 and Orai1 proteins.
authors.affiliation: EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François Rabelais, IFR-136 Agents Transmissibles et Infectiologie, UFR de Médecine, Tours, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Félix
authors.forename: David
authors.initials: D
authors.lastname: Crottès
authors.forename: Anthony
authors.initials: A
authors.lastname: Delalande
authors.forename: Jérémy
authors.initials: J
authors.lastname: Fauconnier
authors.forename: Yvon
authors.initials: Y
authors.lastname: Lebranchu
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Guennec
authors.forename: Florence
authors.initials: F
authors.lastname: Velge-Roussel
mesh_terms: D000943:Antigens, Differentiation / Q000378:metabolism; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000071740:ORAI1 Protein; D034741:RNA, Small Interfering / Q000235:genetics; D000071737:Stromal Interaction Molecule 1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000943:Antigens, Differentiation; D001896:Boron Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D016207:Cytokines; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D034741:RNA, Small Interfering; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D014409:Tumor Necrosis Factor-alpha; C109986:2-aminoethoxydiphenyl borate; D002118:Calcium