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Cited by 91Mitochondrial Function and PathologyT-cell and B-cell ImmunologyCytokine Signaling Pathways and Interactions

Mitochondrial Ca2+ and membrane potential, an alternative pathway for interleukin 6 to regulate CD4 cell effector function

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Yang, Rui, Lirussi, Dario, Thornton, Tina M, Jelley-Gibbs, Dawn M, Diehl, Sean A, Case, Laure K, Madesh, Muniswamy, Taatjes, Douglas J +3 more·2015·eLife
DOI 10.7554/elife.06376PMC PMC4447996
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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 Ca2+ late during activation of CD4 cells. Increased levels of mitochondrial Ca2+ 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 Ca2+ is an alternative pathway by which IL-6 regulates effector function of CD4 cells and it could contribute to the pathogenesis of inflammatory diseases.

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  • mtSTAT3 contributes to maintaining late expression of IL-4 and IL-21 through increases in mitochondrial calcium levels and ATP.

    “mtSTAT3 contributes to maintaining their late expression through increases in mitochondrial calcium levels and ATP”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Yang et al., 2015

    The Results section on mitochondrial Ca2+ and late cytokine production links Stat3 and mitochondrial Ca2+ to sustained IL-21 and IL-4 production in activated CD4 cells. But the Results section on mitochondrial hyperpolarization reports that IL-6 did not increase intracellular or extracellular ATP, contrary to the claimed ATP increase. Page numbers are unavailable in our copy. (LLM, conf=0.90)

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Cited by

Sorted by citations

Authors
Yang, R., Lirussi, D., Thornton, T. M., Jelley-Gibbs, D. M., Diehl, S. A., Case, L. K., Madesh, M., Taatjes, D. J., Teuscher, C., Haynes, L., & Rincón, M.
Affiliations
  • University of Vermont (US)
  • Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
  • Trudeau Institute, Saranac Lake, United States
  • Temple University (US)
  • Trudeau Institute (US)
Corresponding author
Rincón, Mercedes
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2015-05-14
Volume
4
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.06376
PMC
PMC4447996
OpenAlex
W2103638873
Cited by
91
References
6
Citations by year
2026: 2 · 2025: 6 · 2024: 9 · 2023: 9 · 2022: 9 · 2021: 10 · 2020: 13 · 2019: 8 · 2018: 10 · 2017: 7 · 2016: 6 · 2015: 2
FWCI
3.62
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • HZI (Helmholtz Centre for Infection Research) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • TUScholarShare (Temple University) (submittedVersion, public-domain)
Funders
National Institutes of Health (NIH) (R56AI094027, P20GM103496, RR019246-01)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
interleukin-6, CD4+ T cells, T cell effector function, mitochondrial calcium, mitochondrial membrane potential, mitochondrial hyperpolarization, respiratory chain supercomplexes, mitochondrial uncoupling, T cell activation, inflammatory diseases
MeSH terms
Interleukin-21, Animals, Calcium, Interleukins, Membrane Potentials, Mice, Inbred C57BL, Mitochondria, Signal Transduction, CD4-Positive T-Lymphocytes, Interleukin-6, Mice, Knockout, Calcium Signaling, Vesicular Transport Proteins, Mitochondrial Membranes, Mice

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