Redox-sensitive signaling system Кeap1/Nrf2/ARE in differentiation and activation of Т lymphocytes
Activation of the protective intracellular signaling system Keap1/Nrf2/ARE has been studied during Th1 immune response induced by transfer of allogeneic T lymphocytes from donor mice strain C57Bl6/J to F1 hybrid mice (C57Bl6/J ´ DBA/2)F1. Activation of donor T cells by MHC antigens expressed on antigen-presenting recipient cells, its clonal expansion and differentiation into effector cells induce acute graft-versus-host reaction (GVHR). Alloreactive T lymphocytes have been shown to enhance generation of reactive oxygen species in acute GVHR, most likely – due to activation of the cell superoxide-generating systems. The observed increase in the synthesis of reactive oxygen species leads to the stabilization of transcription factor Nrf2, resulting in elevation of its concentration in T lymphocytes. Increased Nrf2 half-life Т1/2 is a key event in activation of the signaling system Keap1/Nrf2/ARE and with translocation of transcription factor molecules into the cell nucleus determines the expression of target genes. In accordance with the findings of Nrf2 stabilization the synthesis of protein products of ARE-regulated genes gsta, nqo1 and gclm has also been shown to increase. In addition, it was found that when mice T lymphocytes are activated in vitro by mitogen following Nrf2 induction by phenolic antioxidants, the production of key Th1-dependent cytokine IFN-γ does not change, although the synthesis of other pro-inflammatory mediator IL-17A, on the contrary, increases. Overall, the data suggest the involvement of the signaling system Keap1/Nrf2/ARE in the lymphocyte activation and differentiation in model systems in vitro and in vivo, although the effects of induction of this signaling pathway require further investigation.
About Authors (Correspondence):
Chechushkov A.V. – researcher of laboratory of cell physiology and pathology molecular mechanisms, e-mail: firstname.lastname@example.org
Tkachev V.O. – candidate of biological sciences, senior researcher of laboratory of cell physiology and pathology molecular mechanisms, e-mail: email@example.com
Zenkov N.K. – doctor of biological sciences, leading researcher of group for free-radical processes, e-mail: firstname.lastname@example.org
Menshchikova E.B. – doctor of medical sciences, head of group for free-radical processes, e-mail: email@example.com