Atorvastatin interferes with activation of human CD4+ T cells via inhibition of small guanosine triphosphatase (GTPase) activity and caspase-independent apoptosis

Abstract

SummaryAlthough a beneficial effect of hydroxy-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors, i.e. statins, on cell-mediated immunity has been suggested in vivo and in vitro, little is known about the molecular and biochemical events by which statins inhibit T cell proliferation. To address this question, we investigated the effects of atorvastatin (AT) on intracellular cytokine production, T cell activation markers, cell cycle progression and apoptosis in human CD4 + T cells. AT did not influence intracellular cytokine production after short-term stimulation of whole blood with phorbol myristate acetate (PMA)/ionomycin or superantigen (SEB). In contrast, AT influenced CD45RA to RO switching dose-dependently, as well as CD25 expression, and caused cell cycle arrest in the G1 phase after long-term T cell stimulation. This occurred in conjunction with a reduced expression of cyclin-dependent kinases 2 and 4 and p21 wav1/cip1 and was paralleled by an increased protein expression of p27 kip1 . In addition to G1 arrest, increased apoptosis was observed in AT-treated cells. In line with this, the expression of Bcl-xl and pBad were decreased by AT. Apoptosis was independent of caspases 3 and 9 activation. The inhibitory effect of AT on T cell proliferation could be overcome by addition of mevalonic acid or geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate or squalen, suggesting reduced protein prenylation. Activation of Rho, Rac and Ras were strongly reduced in AT-treated T cells, suggesting that impaired geranylation of these molecules might underlie the inhibitory effect of AT on T cell proliferation.

Statin effects on regulatory and proinflammatory factors in chronic idiopathic urticaria

“…*P < 0·05; **P < 0·01; ***P < 0·001. proliferation involves the impaired geranylation of Rho, Rac and Ras GTPases, whereas the early T cell activation markers seem not to be affected by atorvastatin [24].…”

“…Usually, apoptosis takes place by strong stimulation, such as PMA/ionomycin in CD4 + T cells, in the presence of atorvastatin (10 mm) [24] or fluvastatin (10 mm) in resting CD4 + T cells, but not in CD4 + T cells that are strongly activated with high concentrations of PMA/ionomycin [25].…”

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

“…Simvastatin reduces cellularity of peripheral lymphoid organs in mice by inhibiting lymphocyte homing Statins have been reported to enhance apoptosis of both human and murine lymphocytes in vitro [5,[20][21][22]; however, little is known about the pro-apoptotic activities of statins in vivo and [23,24], has no adverse effects on liver function [24,25]. At autopsy, spleen and lymph nodes from simvastatin-treated mice were found to be significantly reduced in size compared with carrier-treated mice, which was associated with reduced cellularity.…”

“…Statins inhibit T-cell activation, cell cycle progression and proliferation, as well as migration, both through an HMG-CoA-reductase-independent mechanism, involving allosteric inhibition of LFA-1 [3] and HMGCoA-reductase-dependent mechanisms, which rely on their capacity to inhibit prenylation of small GTPases [4,5]. Moreover, recent reports have provided evidence that some statins also affect helper T-cell differentiation by promoting Th2 polarization and suppressing Th1 polarization both in vitro and in vivo [6,7].…”

Donor statin treatment protects against severe acute graft-versus-host disease after related allogeneic hematopoietic cell transplantation

“…[1][2][3] Statins have been shown to affect immune responses through a variety of mechanisms, including induction of T-cell hyporesponsiveness by interference with intracellular signaling pathways, expansion of regulatory T cells (Treg), polarization toward an anti-inflammatory T cell phenotype (Th2), and downregulation of antigen-presenting cell (APC) function. [4][5][6][7][8][9][10][11] Zeiser et al observed reduced mortality related to acute GVHD when either donor or recipient mice were given atorvastatin for 10 days before major histocompatibility complex (MHC)-mismatched allogeneic HCT. 6 Statin pretreatment of both donor and recipient enhanced the protective effect against acute GVHD-associated mortality in this study.…”