Dataset Information

Vitamin D and IFN-? Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes.

ABSTRACT: IFN-? treatment is a commonly used therapy for relapsing-remitting multiple sclerosis (MS), while vitamin D deficiency correlates with an increased risk of MS and/or its activity. MS is a demyelinating chronic inflammatory disease of the central nervous system, in which activated T lymphocytes play a major role, and may represent direct targets of IFN-? and vitamin D activities. However, the underlying mechanism of action of vitamin D and IFN-?, alone or in combination, remains incompletely understood, especially when considering their direct effects on the ability of T lymphocytes to produce inflammatory cytokines. We profiled the expression of immune-related genes and microRNAs in primary human T lymphocytes in response to vitamin D and IFN-?, and we dissected the impact of these treatments on cytokine production and T cell proliferation. We found that the treatments influenced primarily memory T cell plasticity, rather than polarization toward a stable phenotype. Moreover, our data revealed extensive reprogramming of the transcriptional output of primary T cells in response to vitamin D and IFN-? and provide the bases for further mechanistic insights into these commonly used treatments.

SUBMITTER: Bianchi N

PROVIDER: S-EPMC7746617 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Vitamin D and IFN-β Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes.

Bianchi Niccolò N Emming Stefan S Zecca Chiara C Monticelli Silvia S

Frontiers in immunology 20201204

IFN-β treatment is a commonly used therapy for relapsing-remitting multiple sclerosis (MS), while vitamin D deficiency correlates with an increased risk of MS and/or its activity. MS is a demyelinating chronic inflammatory disease of the central nervous system, in which activated T lymphocytes play a major role, and may represent direct targets of IFN-β and vitamin D activities. However, the underlying mechanism of action of vitamin D and IFN-β, alone or in combination, remains incompletely unde ...[more]

PMID: 33343562

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Project description:BackgroundThe NF-?B signaling pathway orchestrates many of the intricate aspects of neuroinflammation. Astrocytic ??-adrenergic receptors have emerged as potential regulators in central nervous system inflammation and are potential targets for pharmacological modulation. The aim of this study was to elucidate the crosstalk between astrocytic ??-adrenergic receptors and the TNF-? induced inflammatory gene program.MethodsProinflammatory conditions were generated by the administration of TNF-?. Genes that are susceptible to astrocytic crosstalk between ??-adrenergic receptors (stimulated by clenbuterol) and TNF-? were identified by qPCR-macroarray-based gene expression analysis in a human 1321 N1 astrocytoma cell line. Transcriptional patterns of the identified genes in vitro were validated by RT-PCR on the 1321 N1 cell line as well as on primary rat astrocytes. In vivo expression patterns were examined by intracerebroventricular administration of clenbuterol and/or TNF-? in rats. To examine the impact on the inflammatory cell content of the brain we performed extensive FACS analysis of rat brain immune cells after intracerebroventricular clenbuterol and/or TNF-? administration.ResultsParallel transcriptional patterns in vivo and in vitro confirmed the relevance of astrocytic ??-adrenergic receptors as modulators of brain inflammatory responses. Importantly, we observed pronounced effects of ?2-adrenergic receptor agonists and TNF-? on IL-6, CXCL2, CXCL3, VCAM1, and ICAM1 expression, suggesting a role in inflammatory brain cell homeostasis. Extensive FACS-analysis of inflammatory cell content in the brain demonstrated that clenbuterol/TNF-? co-administration skewed the T cell population towards a double negative phenotype and induced a shift in the myeloid brain cell population towards a neutrophilic predominance.ConclusionsOur results show that astrocytic ??-adrenergic receptors are potent regulators of astrocytic TNF-?-activated genes in vitro and in vivo, and ultimately modulate the molecular network involved in the homeostasis of inflammatory cells in the central nervous system. Astrocytic ??-adrenergic receptors and their downstream signaling pathway may serve as potential targets to modulate neuroinflammatory responses.

Dataset Information

Vitamin D and IFN-? Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes.

Publications

Vitamin D and IFN-β Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes.

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