Statin Modulation of Human T-Cell Proliferation, IL-1 and IL-17 Production, and IFN- T Cell Expression: Synergy with Conventional Immunosuppressive Agents
HMG-CoA reductase inhibitors (statins) have been demonstrated to be immunomodulatory for human immune-mediated disease and in experimental models. The aim of this study was to compare statin-mediated immunosuppressive effects on human T-cell responses in vitro with those of conventional immunosuppressives (dexamethasone, cyclosporin A (CsA), mycophenolate, and rapamycin). Statins (atorvastatin, lovastatin, and simvastatin) were investigated for their modulatory effects on human PBMC viability, cytokine profiles, and T-cell proliferation. At concentrations that inhibited anti-CD3/28-stimulated T-cell proliferation ( ), simvastatin significantly decreased intracellular CD4+ T-cell expression of IFN- ( ) to levels similar to those induced by conventional immunosuppressives. Atorvastatin and lovastatin also decreased IFN- expression, although to a lesser degree ( ). All three statins reduced levels of IL-17 production ( ). However, in response to anti-CD3/28 stimulation, simvastatin significantly upregulated IL-1 production ( ). The profile of cytokines produced in response to anti-CD3/28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone, suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines. This data supports the hypothesis of selective statin-mediated immunomodulatory effects on human immune cells. 1. Introduction As a therapy for hypercholesterolaemia, statins have been used clinically for over two decades. However, over the last decade, immunosuppressive effects have also been demonstrated which are independent of their cholesterol-lowering properties [1]. Statins in vitro modulate cell adhesion through effects on endothelial cells and leukocytes, via blocking activation of LFA-1 and decreasing ICAM-1 and MCP-1 expression on activated leukocytes and endothelium [2–4]. Statins have been shown in vitro and in vivo to reduce leukocyte motility, migration, and infiltration [5]. As compared to cyclosporine, statins were effective in reducing leukocyte infiltration in a rat model of allograft rejection [6]. They also inhibit the NF- B pathway, involved in transcriptional regulation of cytokines, chemokines, and adhesion molecules [7]. Statins have been shown to upregulate suppressor of cytokine secretion (SOCS) 3 and SOCS 7 which, in turn, downregulate IL-23 and IL-6 production, thus decreasing IL-17 production [8]. Clinical studies of statins in patients with immune-mediated diseases such as rheumatoid arthritis (RA), multiple sclerosis, and
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