Blocking of Type 1 Angiotensin II Receptor Inhibits T-lymphocyte Activation and IL-2 Production

Abstract

Background/Aim: Novel information on the role of endogenous compounds in regulating physiological and pathological process are of interest, as it may lead to the development of better strategies for disease management. The role of angiotensin II and the signaling of type 1 angiotensin II receptor (AGT1R) in T-lymphocyte activation and interleukin-2 (IL-2) production are largely unknown. Materials and Methods: Jurkat T-cells were treated with AGT1R inhibitor candesartan and stimulated with phorbol myristate acetate (PMA) and ionomycin. T-Cell activation, associated cytokine production and levels of signaling proteins were evaluated by flow cytometry and western blot analysis. Results: Candesartan significantly suppressed PMA and ionomycin-induced CD25 expression and IL-2 production. Regarding the molecular mechanism involved, we showed that such suppressive effects of blocking of AGT1R by candesartan resulted in the significant inhibition of ERK activation in PMA-stimulated Jurkat T-cells. The effect of ERK inhibition on T-cell activation was further confirmed. Treatment with FR180204, a specific ERK inhibitor, reduced T-cell activation and IL-2 secretion. Conclusion: AGT1R signaling is essential for T-cell activation and IL-2 production, and the inhibition of this pathway suppressed T-cell activation via an ERK-dependent mechanism.

Angiotensin II Type I Receptor (AT1R): The Gate towards COVID-19-Associated Diseases

“…Ang II has been shown to play a role in regulating the immune system ( Figure 4 ). In fact, AT1R is found on the surface of a variety of immune cells, including T cells, which possess endogenous RAS, express functional RAS components, and locally produce Ang II [ 42 , 43 , 44 ]. The latter promotes immune cells’ proliferation, migration, differentiation, adhesion, and effector function, and acts as a costimulatory molecule important for T-cell activation.…”

“…The proportion of patients with elevated levels of these proteins in the severe group was significantly higher than in the mild group [ 41 ]. Tawinwung et al have shown that AT1R signaling is essential for T-cell activation and IL-2 production, and the inhibition of this pathway suppressed T-cell activation via an ERK-dependent mechanism [ 43 ].…”

Immunomodulatory Activity of the Most Commonly Used Antihypertensive Drugs—Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

“…Furthermore, candesartan inhibits inflammation by modulating signaling cascades dependent on TNF-α, IL-1beta, IL-2, IL-6, TGF-β, and NF-κB. In addition, it reduces the formation of ROIs by phagocytes and lowers the expression of CD25 and IL-2 release by T cells [113,[124][125][126][127][128][129]. However, this medicament seems to not affect the secretion of IL-10 [130], similarly to olmesartan [121].…”

“…-IL-1beta [31], IL-6 and IL-8 concentration [31,32,85]; -CRP concentration [41]; -TNF-alfa concentration [41,113,[124][125][126][127][128][129]; -lymphocyte proliferation and IFN-gamma production in vitro assays, and suppressed antigen-specific Th1 and Th2 lymphocytes in vivo [115]; -formation of ROIs by phagocytes [113,[124][125][126][127][128][129]; -the expression of CD25 and IL-2 release by T cells [113,[124][125][126][127][128][129]; -the general number of immune cells in bronchoalveolar lavage fluid [125]; -the release of Th2-lymphocyte (IL-4, IL-5 and IL-13) and Th1-lymphocyte (IL-2 and IFN-γ) cytokines [125].…”

Induced dysregulation of ACE2 by SARS-CoV-2 plays a key role in COVID-19 severity

“…A previously-published study has reported that downregulation of ACE2 in macrophages in COVID-19 patients increases the inflammatory cytokine and production of NO. On the other hand, Ang II induces cell proliferation and cytokine production implying the role of Ang II in regulating the cell signaling in inflammation and immune-related diseases [186]. IL-2 is an immune cytokine that stimulates the proliferation of T cells [187].…”