title: Mitochondrial Ca²⁺ and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function.
abstract: IL-6 plays an important role in determining the fate of effector CD4 cells and the cytokines that these cells produce. Here we identify a novel molecular mechanism by which IL-6 regulates CD4 cell effector function. We show that IL-6-dependent signal facilitates the formation of mitochondrial respiratory chain supercomplexes to sustain high mitochondrial membrane potential late during activation of CD4 cells. Mitochondrial hyperpolarization caused by IL-6 is uncoupled from the production of ATP by oxidative phosphorylation. However, it is a mechanism to raise the levels of mitochondrial Ca(2+) late during activation of CD4 cells. Increased levels of mitochondrial Ca(2+) in the presence of IL-6 are used to prolong Il4 and Il21 expression in effector CD4 cells. Thus, the effect of IL-6 on mitochondrial membrane potential and mitochondrial Ca(2+) is an alternative pathway by which IL-6 regulates effector function of CD4 cells and it could contribute to the pathogenesis of inflammatory diseases.
authors.affiliation: Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States.
authors.forename: Dario
authors.initials: D
authors.lastname: Lirussi
authors.affiliation: Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Thornton
authors.affiliation: Trudeau Institute, Saranac Lake, United States.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Jelley-Gibbs
authors.affiliation: Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Diehl
authors.affiliation: Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States.
authors.forename: Laure K
authors.initials: LK
authors.lastname: Case
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Temple University, Philadelphia, United States.
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, United States.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Taatjes
authors.affiliation: Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States.
authors.forename: Cory
authors.initials: C
authors.lastname: Teuscher
authors.affiliation: Trudeau Institute, Saranac Lake, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Haynes
authors.affiliation: Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rincón
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D051336:Mitochondrial Membranes / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D033921:Vesicular Transport Proteins; D000098546:Interleukin-21
chemical_list: D015850:Interleukin-6; D007378:Interleukins; C545985:TXLNA protein, mouse; D033921:Vesicular Transport Proteins; D000098546:Interleukin-21; D002118:Calcium
keywords: IL-6; NFATc2; Stat3; calcium; effector cytokines; immunology; mitochondrion; mouse