Effects of lovastatin on natural killer cell function and other immunological parameters in man

Abstract

Suppression of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, such as lovastatin, has been shown to inhibit mitogen stimulated proliferation of natural killer (NK) cells and other lymphocytes in vitro. This effect is only partially overcome by provision of exogenous free or lipoprotein cholesterol but is reversed by mevalonate, suggesting that proliferating lymphocytes have a specific requirement for a nonsterol isoprenoid product of mevalonate. The effect of lovastatin (20 mg bid) on a range of immune function parameters was determined in a randomized, placebo-controlled, double-blind ex vivo study in 52 patients with primary hypercholesterolemia. No significant differences (P < 0.05) were found between lovastatin and placebo groups for basal NK or interleukin-2 (IL-2)-induced cell-mediated cytotoxicity, PHA-stimulated lymphocyte proliferation, or relative numbers of T lymphocytes (CD3+), B lymphocytes (CD19+), total NK cells (CD3-, CD16+, CD56+) and CD57+ NK cells or in immunoglobulin levels after 4 or 8 weeks of treatment. In contrast to previous in vitro data, no statistically or clinically significant changes were observed in any parameter of lymphocyte function in patients treated with lovastatin.

Lovastatin inhibits brain endothelial cell Rho‐mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis

“…Moreover, in ABH mice we were unable to observe a dramatic attenuation of leucocyte infiltration into the skin during a DTH response. Indeed, it has been shown previously that potent peripherally-acting immunosuppressive agents have only a marginal effect on disease relapse in this model (18), and that significant immunosuppression has not been observed in statin-treated humans (23). It has also been proposed that alterations in matrix metalloprotease (MMP) secretion (34) may alter lymphocyte endothelial cell interactions.…”

“…There are a number of reports demonstrating that statins have anti-proliferative activity in vitro (22,23). Such potential immunosuppression could account for the ameliorative effects of lovastatin, particularly when statins are administered during the sensitisation period, as occurred previously in MBP-induced hyperacute EAE (24,25).…”

The Symptomatic Carotid Plaque

“…There is increased collagen and decreased inflammatory cells, MMPs, and proteolytic activity in the fibrous cap. 67 Statins also have a range of other potential benefits, including improved endothelial function, 68 reduction in hypercoagulability, 69 and beneficial modulation of immune function, 70 which likely contributes to their effect in stroke reduction.…”

Simvastatin Initiated Early After Heart Transplantation

“…Thus, statins were shown to result in reduced natural killer cell activity in vitro. 22,23 In addition, T-cell proliferation and T lymphocyte cytotoxicity were inhibited. 24 Other reported immunomodulating effects of statins in the presence of cyclosporin A include suppression of T-cell responses, reduction of chemokine synthesis by mononuclear cells in the peripheral bloodstream, and inhibition of the expression of MHC-II genes.…”