Glucocorticoid receptors in lymphocytes and stability of kidney graft function

Abstract

The glucocorticoid receptors in lymphocytes of patients treated with glucocorticoids after kidney transplantation have been studied in order to determine whether abnormalities in corticosteroid binding and trans-activation of steroid-receptor complexes, i.e., their translocation into nuclei, may contribute to the resistance of patients to glucocorticoid therapy. The patients were divided into two groups, according to graft stability: patients with stable graft function and those with chronic allograft rejection. The study revealed changes in both level and binding affinity of glucocorticoid receptors in peripheral blood lymphocytes from patients with chronic graft rejection, compared with control level, as well as with values of patients with stable graft function. These data indicate that sensitivity to glucocorticoids depends, at least in part, on the alterations of glucocorticoid receptors. The receptor translocation into nuclei indicates that unknown post-receptor events might also be involved in glucocorticoid resistance that seriously impair successive glucocorticoid therapy after organ transplantation. Further examination of glucocorticoid receptors in cases of organ transplantation seems warranted.

Steroid regulation: An overlooked aspect of tolerance and chronic rejection in kidney transplantation

“…Published reports indicate that peripheral blood lymphocytes from CR patients show lower number of GR binding cites and lower GR affinity for GC compared to stable patients (Ribarac-Stepic et al, 2001), which would be in agreement with our findings of a negative association of NR3C1 expression with T and B-cell counts. The positive association of NR3C1 expression with neutrophil counts may explain why we have observed a net increase in NR3C1 expression in whole blood samples from CR compared to stable patients ( Figure 1D, Figure 2B).…”

“…Given the high importance of GC action for transplantation outcomes and the importance of endogenous GC conversion for GC action, it is surprising that studies on the role of endogenous GC conversion and GC response independent of exogenous GC administration are scarce in transplantation research and that largely only the effects of exogenous steroids on lymphocyte populations have been considered (Berki et al, 2002,Ribarac-Stepic et al, 2001).…”

Molecular basis of glucocorticoid action

“…Naime, iako glikokortikoidi smawuju broj limfocita, kako redistribucijom limfocita u limfnim čvorovima, tako i indukcijom apoptoze limfocita i supresije timusa [8], ove funkcije su nedovoqne da objasne imunosupresivno delovawe glikokortikoida. Međutim, iako tačan mehanizam lize i smawewa broja limfoidnih ćelija nije jasan, dokazano je da su i imunosupresivni efekti glikokortikoida posredovani glikokortikoidnim receptorima [9,10]. Pokazano je da je veliki broj receptora u limfoidnim ćelijama u korelaciji s pozitivnim kliničkim odgovorom na glikokortikoidnu terapiju [11].…”

“…Pored genske mutacije GR, rezistencija, odnosno smawena osetqivost na delovawe GH može biti i zbog promena na nivou receptora koje nastaju u nekim patološkim stawima, kao što su maligna transformacija, neoplazija, Kušingov (Cushing) sindrom, sida, astma, reumatoidni artritis i dr. Takođe, u stawima kao što su depresija, sepsa i stres dolazi do promena u koncentraciji i osobinama GR koje imaju za posledicu promewenu senzitivnost na delovawe GH [15,30]. Poznati su i slučajevi glikokortikoidne rezistencije izazvane farmakološkim sredstvima kod terapijske primene glikokortikoida [10,31], ali i u stawima povećane koncentracije cirkulišućeg kortizola [32]. Ova zapažawa su u saglasnosti s rezultatima koji pokazuju da povećawe glikokortikoida smawuje koncentraciju GR [33,34].…”

Dexamethasone has pro‐apoptotic effects on non‐activated fresh peripheral blood mononuclear cells

“…It is well known that apoptosis can be induced by a variety of agents, including dexamethasone (DEX), a synthetic glucocorticoid endowed with anti-inflammatory and immuno-suppressive properties, which probably result from its ability to induce apoptosis in immune cells (Schimidt et al, 2001;Yoshimura et al, 2001). Because of these properties, DEX is widely used in the treatment of autoimmune diseases (Ho et al, 2001) and allergic disorders (Sun et al, 1998), as well as in co-adjuvant drugs for cancer therapy (Herr et al, 2003) and immunomodulation of transplant patients (Ribarac-Stepic et al, 2001). Thus, it has been suggested that DEX can play a homeostatic role inducing apoptosis in lymphocytes after activation, and that this takes place through the interaction of DEX with the glucocorticoid receptor that activates the caspases by an intrinsic pathway (Brunetti et al, 1995).…”