Abstract 253: Norepinephrine Suppresses T-lymphocyte Growth and Cytokine Production via Superoxide During Hypertension
Numerous studies have shown that pro-inflammatory cytokines produced by T-lymphocytes exacerbate hypertension. However, it is not clearly understood how endogenous pro-hypertensive stimuli such as norepinephrine (NE) directly act upon T-lymphocytes to modulate the responses of these inflammatory cells during hypertension. Herein, we hypothesized that increased systemic levels of NE directly activate T-lymphocytes during hypertension. To test this hypothesis, we examined the status of T-lymphocyte activation in the spleens of NE-infused hypertensive mice. Contrary to our hypothesis, while subcutaneous infusion of NE (3.8 μg/kg/min) significantly increased mean arterial pressure by approximately 18 ± 2 mmHg for 14-days (p<0.05 vs. saline infused), splenic T-lymphocytes demonstrated no signs of increased activation. More specifically, splenic T-lymphocytes from NE-infused mice showed an approximate 20% ± 5% (p<0.05) decrease in proliferation accompanied by a 50% ± 17% (p<0.05) and 85% ± 6% (p<0.05) reduction in interferon gamma (INFγ) and tumor necrosis factor alpha (TNFα) production respectively as compared to T-lymphocytes from saline-infused mice. Additionally, NE directly inhibited naïve T-lymphocyte proliferation and cytokine production ex vivo in a dose dependent manner. Furthermore, while NE did not demonstrate any pro-apoptotic effects on T-lymphocytes, a 21% ± 2% (p<0.05 vs. saline) increase in G1 arrest was observed in NE-treated T-lymphocytes, and this was accompanied by a 60% ± 4% (p<0.05 vs. saline) decrease in pro-growth cyclin D3, E1, and E2 mRNA expression. Interestingly, NE caused a 71% ± 17% (p<0.05 vs. saline) increase in cellular superoxide (O2•-) production as evidenced by dihydroethidium (DHE) oxidation, which was shown to be partially-causal to the inhibitory effects of NE as the addition of Tempol, a O2•- scavenger, to the drinking water of NE-infused mice was able to moderately restore T-lymphocyte growth and pro-inflammatory cytokine production. Taken together with previous studies, our data indicates that direct NE stimulation of naïve T-lymphocytes inhibits their proliferation and cytokine production in hypertension.
Author Disclosures: A.J. Case: None. M.C. Zimmerman: None.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).
- © 2014 by American Heart Association, Inc.