Non‐genomic rapid inhibition of Na⁺/H⁺‐exchange 1 and apoptotic immunosuppression in human T cells by glucocorticoids

Abstract

Glucocorticoids (GCs) have been employed as immunosuppressive agents for many years. However, it is still unclear how GCs instantly uncouple T cells from acute stressful inflammatory. In terms of time scale, the genomic activity of the classic GC receptor cannot fulfill this role under crisis; but a rapid non-genomic response can. In a previous study, intracellular acidification was found to be due to a rapid non-genomic inhibition of Na(+)/H(+)-exchange 1 (NHE1) and this event led to the immunosuppression of T cell proliferation by progesterone. The aim of this study was to examine whether there is a rapid acidification response caused by an inhibition of NHE1 activity and to explore the differential non-genomic effect on immunosuppression of hydrocortisone and dexamethasone. The IC(50) values for NHE1-dependent pH(i) recovery by hydrocortisone and dexamethasone are 250 and 1 nM, respectively. Co-stimulation of GCs with phytohemagglutinin (PHA) is able to inhibit PHA-induced IL-2 secretion, IL-4 secretion, and T-cell proliferation. Furthermore, apoptosis in PHA-activated T cells is not induced by hydrocortisone but by dexamethasone. The mechanism of immunosuppression on proliferation by dexamethasone was found to be different of hydrocortisone and seems to involve cytotoxicity against T cells. Moreover, apoptosis induced by dexamethasone and impermeable dexamethasone-bovine serum albumin suggests that the apoptotic immunosuppression occurs through both the plasma membrane and cytoplasmic sites. The rapid inhibitory responses triggered by GCs would seem to release T cells instantly when an acute stress-related response is needed. Nonetheless, the apoptotic immunosuppression by dexamethasone is attributable to its severe cytotoxicity.

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

“…Previously, it was suggested that IL-2 signaling could induce NHE1 activity in human T cells (51) as well as in murine T cells (52,53). In extension to these previous findings, our study revealed that each Th cell subset differs in pH i , which is governed by Na ϩ /H ϩ exchanger activity.…”

“…Previous studies in human T cells have suggested that addition of IL-2 to cultured cells could enhance pH i and NHE1 protein abundance, thus affecting cell proliferation, cytokine production, and apoptosis (51). It has been further proposed that pH i and NHE1 activity are modulated by glucocorticoids in a non-genomic fashion (49,(52)(53)(54)(55)(56). However, to which extent pH i and NHE activity govern Th9 cell development and function is incompletely understood.…”

Proteomic profiling of rapid non-genomic and concomitant genomic effects of acute restraint stress on rat thymocytes

“…At least for one of its interactors, the G-protein coupled protein receptor ADRB2 nuclear localization has been shown in the hippocampus [48]. NHERF1 also interacts with Na(+)/H(+)-exchanger 1 (NHE1), an ion transporter that has been shown to be inhibited by rapid non-genomic effects of GC leading to immunosuppression in T cells [49]. This interaction is also interesting since NHE1 has been recently identified as a MAPK scaffold [50].…”

ZAP-70 tyrosines 315 and 492 transmit non-genomic glucocorticoid (GC) effects in T cells

“…For example, in activated murine thymocytes GCs inhibited the activation of Na + -K + -ATPase and Ca 2+ -ATPase (Buttgereit and Scheffold, 2002), and the Na + /H + exchange could also be inhibited with GCs (Chang et al, 2010). Membrane GR expression has been observed first in the S-49 mouse T lymphoma cells and the CCRF-CEM human T cell lymphoblast like cell line, and later on human peripheral lymphocytes and monocytes; however, its exact structure and signaling mechanisms are still unclear (Gametchu et al, 1993).…”