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The ?4 nicotinic receptor promotes CD4+ T-cell proliferation and a helper T-cell immune response.

ABSTRACT: Smoking is a common addiction and a leading cause of disease. Chronic nicotine exposure is known to activate nicotinic acetylcholine receptors (nAChRs) in immune cells. We demonstrate a novel role for ?4 nAChRs in the effect of nicotine on T-cell proliferation and immunity. Using cell-based sorting and proteomic analysis we define an ?4 nAChR expressing helper T-cell population (?4(+)CD3(+)CD4(+)) and show that this group of cells is responsive to sustained nicotine exposure. In the circulation, spleen, bone marrow, and thymus, we find that nicotine promotes an increase in CD3(+)CD4(+) cells via its activation of the ?4 nAChR and regulation of G protein subunit o, G protein regulated-inducer of neurite outgrowth, and CDC42 signaling within T cells. In particular, nicotine is found to promote a helper T cell 2 adaptive immunologic response within T cells that is absent in ?4(-/-) mice. We thus present a new mechanism of ?4 nAChR signaling and immune regulation in T cells, possibly accounting for the effect of smoking on the immune system.

SUBMITTER: Nordman JC

PROVIDER: S-EPMC3868899 | biostudies-other | 2014 Jan

REPOSITORIES: biostudies-other

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The α4 nicotinic receptor promotes CD4+ T-cell proliferation and a helper T-cell immune response.

Nordman Jacob C JC Muldoon Pretal P Clark Sarah S Damaj M Imad MI Kabbani Nadine N

Molecular pharmacology 20131009 1

Smoking is a common addiction and a leading cause of disease. Chronic nicotine exposure is known to activate nicotinic acetylcholine receptors (nAChRs) in immune cells. We demonstrate a novel role for α4 nAChRs in the effect of nicotine on T-cell proliferation and immunity. Using cell-based sorting and proteomic analysis we define an α4 nAChR expressing helper T-cell population (α4(+)CD3(+)CD4(+)) and show that this group of cells is responsive to sustained nicotine exposure. In the circulation, ...[more]

PMID: 24107512

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Project description:BackgroundAging is the most important risk factor for prostate cancer (PCa), but how age contributes to PCa is poorly understood. Aging is characterized by low-grade systemic inflammation (i.e., inflammaging) that is often attributed to the progressive activation of immune cells over time, which may play an important role in prostate carcinogenesis. Th17 response is elevated in aging humans and mice, but it remains unknown whether it is increased in prostate tissue or contributes to prostate carcinogenesis during aging. In this study, we aimed to determine the role of age-related Th17 response in PCa cell growth, migration, and invasion.MethodsC57BL/6J (B6) mouse was used as an aging animal model and the prostate histopathology during aging was analyzed. Splenic CD4+ T cells were isolated from young (16-20 weeks old) and aged (96-104 weeks old) mice, and cultured in the presence of plate-bound anti-CD3/anti-CD28, with or without Th17 differentiation conditions. The cells were collected and used for subsequent flow cytometry or quantitative reverse transcription polymerase chain reaction. The supernatant was collected and used to treat PCa cell lines. The treated PCa cells were analyzed for cell viability, migration, invasion, and nuclear factor kappa B (NF-κB) signaling.ResultsAged mice had enlarged prostate glands and increased morphological alterations, with not only increased inflammatory cell infiltration but also increased Th17 cytokines in prostate tissue, compared to young mice. Naïve CD4+ T cells from aged mice differentiated increased interleukin (IL)-17-expressing cells. CD4+ T cells from aged mice spleen had increased Th17 cells, Th17 cytokines and Th17/Treg ratio compared to young mice. Factors secreted from aged CD4+ T cells, especially from ex vivo differentiated Th17 cells, not only promoted PCa cell viability, migration, and invasion but also activated the NF-κB signaling in PCa cells compared to young mice.ConclusionsThese results indicate that age-related CD4+ T cells, especially Th17 cells-secreted factors have the potential to contribute to prostate carcinogenesis. Our work could prompt further research using autochthonous PCa mouse models at different ages to elucidate the functional role of Th17 response in prostate carcinogenesis during aging.

Dataset Information

The ?4 nicotinic receptor promotes CD4+ T-cell proliferation and a helper T-cell immune response.

Publications

The α4 nicotinic receptor promotes CD4+ T-cell proliferation and a helper T-cell immune response.

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