title: Redox-regulated suppression of splenic T-lymphocyte activation in a model of sympathoexcitation.
abstract: Sympathoexcitation, increased circulating norepinephrine, and elevated levels of reactive oxygen species are driving forces underlying numerous cardiovascular diseases, including hypertension. However, the effects of elevated norepinephrine and subsequent reactive oxygen species production in splenic T-lymphocytes during hypertension are not currently understood. We hypothesized that increased systemic levels of norepinephrine inhibits the activation of splenic T-lymphocytes via redox signaling. To address this hypothesis, we examined the status of T-lymphocyte activation in spleens of a mouse model of sympathoexcitation-driven hypertension (ie, norepinephrine infusion). Splenic T-lymphocytes from norepinephrine-infused mice demonstrated decreased proliferation accompanied by a reduction in interferon gamma and tumor necrosis factor-α production as compared with T-lymphocytes from saline-infused mice. Additionally, norepinephrine directly inhibited splenic T-lymphocyte proliferation and cytokine production ex vivo in a dose-dependent manner. Furthermore, norepinephrine caused an increase in G1 arrest in norepinephrine-treated T-lymphocytes, and this was accompanied by a decrease in pro-growth cyclin D3, E1, and E2 mRNA expression. Interestingly, norepinephrine caused an increase in cellular superoxide, which was shown to be partially causal to the inhibitory effects of norepinephrine, as antioxidant supplementation (ie, Tempol) to norepinephrine-infused mice moderately restored T-lymphocyte growth and proinflammatory cytokine production. Our findings indicate that suppression of splenic T-lymphocyte activation occurs in a norepinephrine-driven model of hypertension due to, at least in part, an increase in superoxide. We speculate that further understanding of how norepinephrine mediates its inhibitory effects on splenic T-lymphocytes may elucidate novel pathways for therapeutic mimicry to suppress T-lymphocyte-mediated inflammation in an array of diseases.
authors.affiliation: From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (A.J.C., M.C.Z.); and Redox Biology Center, University of Nebraska Lincoln (M.C.Z.).
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Case
authors.affiliation: From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha (A.J.C., M.C.Z.); and Redox Biology Center, University of Nebraska Lincoln (M.C.Z.). mczimmerman@unmc.edu.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Zimmerman
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006973:Hypertension / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000494:pharmacology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology*; D013566:Sympathomimetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D013566:Sympathomimetics; D009638:Norepinephrine
keywords: cardiovascular disease; hypertension; immunosuppression; inflammation; norepinephrine; reactive oxygen species; superoxide