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

✍ Scribed by Ching-Pang Chang; Shyi-Wu Wang; Zih-Ling Huang; Olivia Ya-Hsuan Wang; Michael I-Ta Huang; Li-Ming Lu; Der-Cherng Tarng; Chau-Heng Chien; Eileen Jea Chien

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 344 KB
• Volume: 223
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.22070

✦ Synopsis

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. J. Cell. Physiol. 223:679–686, 2010. © 2010 Wiley‐Liss, Inc.