Regulation of T-cell function by endogenously produced angiotensin II

Abstract

The adaptive immune response and, in particular, T cells have been shown to be important in the genesis of hypertension. In the present study, we sought to determine how the interplay between ANG II, NADPH oxidase, and reactive oxygen species modulates T cell activation and ultimately causes hypertension. We determined that T cells express angiotensinogen, the angiotensin I-converting enzyme, and renin and produce physiological levels of ANG II. AT1 receptors were primarily expressed intracellularly, and endogenously produced ANG II increased T-cell activation, expression of tissue homing markers, and production of the cytokine TNF-alpha. Inhibition of T-cell ACE reduced TNF-alpha production, indicating endogenously produced ANG II has a regulatory role in this process. Studies with specific antagonists and T cells from AT1R and AT2R-deficient mice indicated that both receptor subtypes contribute to TNF-alpha production. We found that superoxide was a critical mediator of T-cell TNF-alpha production, as this was significantly inhibited by polyethylene glycol (PEG)-SOD, but not PEG-catalase. Thus, T cells contain an endogenous renin-angiotensin system that modulates T-cell function, NADPH oxidase activity, and production of superoxide that, in turn, modulates TNF-alpha production. These findings contribute to our understanding of how ANG II and T cells enhance inflammation in cardiovascular disease.

Free Fatty Acid Causes Leukocyte Activation and Resultant Endothelial Dysfunction Through Enhanced Angiotensin II Production in Mononuclear and Polymorphonuclear Cells

“…These results, together with clear experimental evidence that MPO impairs NO availability in an H 2 O 2 -dependent manner, 23 suggest that RAS-mediated leukocyte activation by FFA may facilitate endothelial dysfunction partly through the release of MPO and possibly enhanced leukocyte adhesion. It is reasonably assumed that the release of cytokines and reactive oxygen species from activated T lymphocytes, which has been shown to be Ang dependent, 30 may also adversely modulate vascular function. 31 The extrapolation of our results to patients with visceral fat obesity is not necessarily straightforward.…”

The sympathetic nervous system and blood pressure in humans: implications for hypertension

“…The sympathetic nervous system and RAS share a number of common pro-hypertensive actions (for example, increased vascular resistance and endothelial dysfunction) and both have been implicated in activating the immune system. 60,121,122 Primary hypertension is associated with increased circulating concentration of several inflammatory molecules such as tumour necrosis factor alpha (TNFa), interleukin-6, C-reactive protein and adhesion molecules (for example, P-selectin and intercellular adhesion molecule-1), and vascular inflammation may contribute to the pathophysiology of hypertension. 88,123,124 T-lymphocytes appear particularly critical for Ang II and deoxycorticosterone acetate-salt-induced hypertension and the concomitant vascular and kidney dysfunction.…”

“…88,123,124 T-lymphocytes appear particularly critical for Ang II and deoxycorticosterone acetate-salt-induced hypertension and the concomitant vascular and kidney dysfunction. 121,122,125 T-cell activation is increased by Ang II and leads to the production of pro-inflammatory cytokines. 121 Intriguingly, anti-TNFa therapy (etanercept) has been shown to prevent Ang II-induced hypertension and vascular oxidative stress.…”

Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury

“…Recently, a number of studies have demonstrated that RAS activation could play an important role in immunologically induced inflammation (14)(15)(16). In vitro and in vivo studies have shown that Ang II could induce DCs maturation (14,17).…”

“…In vitro and in vivo studies have shown that Ang II could induce DCs maturation (14,17). Additionally, several lines of evidence demonstrate that Ang II induces Th1 and Th17 immune responses and ultimately enhances inflammation in several Ang II-mediated inflammatory diseases (15)(16)(17)(18). However, the direct regulatory effect of losartan on the function of lung DCs and Th cells in ALI remains to be fully elucidated.…”