Cited by 317T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisCytokine Signaling Pathways and Interactions

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The locus ceruleus norepinephrine system: Functional organization and potential clinical significance

Benarroch, Eduardo E.·2009·Neurology

DOI 10.1212/wnl.0b013e3181c2937c

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Abstract

IL-9–producing Th cells, termed Th9 cells, contribute to immunity against parasites and cancers but have detrimental roles in allergic disease and colitis. Th9 cells differentiate in response to IL-4 and TGF-β, but these signals are insufficient to drive Th9 differentiation in the absence of IL-2. IL-2–induced STAT5 activation is required for chromatin accessibility within Il9 enhancer and promoter regions and directly transactivates the Il9 locus. STAT5 also suppresses gene expression during Th9 cell development, but these roles are less well defined. In this study, we demonstrate that human allergy-associated Th9 cells exhibited a signature of STAT5-mediated gene repression that is associated with the silencing of a Th17-like transcriptional signature. In murine Th9 cell differentiation, blockade of IL-2/STAT5 signaling induced the expression of IL-17 and the Th17-associated transcription factor Rorγt. However, IL-2–deprived Th9 cells did not exhibit a significant Th17- or STAT3-associated transcriptional signature. Consistent with these observations, differentiation of IL-17–producing cells under these conditions was STAT3-independent but did require Rorγt and BATF. Furthermore, ectopic expression of Rorγt and BATF partially rescued IL-17 production in STAT3-deficient Th17 cells, highlighting the importance of these factors in this process. Although STAT3 was not required for the differentiation of IL-17–producing cells under IL-2–deprived Th9 conditions, their prolonged survival was STAT3-dependent, potentially explaining why STAT3-independent IL-17 production is not commonly observed in vivo. Together, our data suggest that IL-2/STAT5 signaling plays an important role in controlling the balance of a Th9 versus a Th17-like differentiation program in vitro and in allergic disease.

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Authors: Benarroch, E. E.
Affiliations: Mayo Clinic (US)
Corresponding author: Benarroch, Eduardo E.
ORCID: Benarroch, Eduardo E.
Venue: Neurology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2009-11-17
Volume: 73
Issue: 20
Pages: 1699-1704
ISSN: 0028-3878 (ISSN-L)
1526-632X
DOI: 10.1212/wnl.0b013e3181c2937c
OpenAlex: W1969610953
Cited by: 317
References: 29
Citations by year: 2026: 14 · 2025: 17 · 2024: 17 · 2023: 32 · 2022: 23 · 2021: 24 · 2020: 32 · 2019: 22 · 2018: 32 · 2017: 17 · 2016: 16 · 2015: 13 · 2014: 19 · 2013: 9 · 2012: 13
FWCI: 4.31
Type: journal article
Language: en
Open access: closed
Locations: Neurology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Keywords: locus coeruleus, norepinephrine, noradrenergic neurons, noradrenergic neurotransmission
MeSH terms: Alzheimer Disease, Animals, Arousal, Attention, Brain, Humans, Locus Coeruleus, Memory, Neural Pathways, Neurons, Norepinephrine, Parkinson Disease, Stress, Psychological, Prosencephalon

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The locus ceruleus norepinephrine system: Functional organization and potential clinical significance

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