Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site

Abstract

The beta2 integrin leukocyte function antigen-1 (LFA-1) has an important role in the pathophysiology of inflammatory and autoimmune diseases. Here we report that statin compounds commonly used for the treatment of hypercholesterolemia selectively blocked LFA-1-mediated adhesion and costimulation of lymphocytes. This effect was unrelated to the statins' inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase; instead it occurred via binding to a novel allosteric site within LFA-1. Subsequent optimization of the statins for LFA-1 binding resulted in potent, selective and orally active LFA-1 inhibitors that suppress the inflammatory response in a murine model of peritonitis. Targeting of the statin-binding site of LFA-1 could be used to treat diseases such as psoriasis, rheumatoid arthritis, ischemia/reperfusion injury and transplant rejection.

Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

“…Soluble ICAM-1 has been shown to interact with the leukocyte ␤ 2 integrin (LFA-1), and it has been proposed as a useful marker of the inflammatory response (64). Closely related to this mechanism, statins have been shown to suppress the inflammatory response by binding directly to a regulatory site of the LFA-1 ␤ 2 integrin, which serves as a major counterreceptor for ICAM-1 on leukocytes (24).…”

“…Statins have also been shown to modify the function of ECs, smooth muscle cells, platelets, and monocytes/macrophages (22). Their effects include decreasing the expression of adhesion molecules in monocytes and leukocyte-endothelial interactions (23)(24)(25)(26), inhibiting platelet function (27), inhibiting tissue factor expression by mononuclear cells (28,29), down-regulating inflammatory cytokines in ECs (30), increasing fibrinolytic activity (31,32), and immunomodulation by decreasing the expression of class II major histocompatibility complex antigen (33).…”

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

“…Statins prevent experimental T helper 1 (Th1)-mediated autoimmune diseases [95] and induce IL-4-dependent Th2-cell differentiation [96] and the secretion of antiinflammatory Th2-type cytokines [97]. Finally, statins can also bind to a novel allosteric site within the β 2 -integrin function-associated antigen-1 protein, independent of mevalonate production [98]. Inhibition of β 2 -integrin function-associated antigen-1 can decrease lymphocyte adhesion to ICAM-1 and impair T-cell co-stimulation [98].…”

“…Finally, statins can also bind to a novel allosteric site within the β 2 -integrin function-associated antigen-1 protein, independent of mevalonate production [98]. Inhibition of β 2 -integrin function-associated antigen-1 can decrease lymphocyte adhesion to ICAM-1 and impair T-cell co-stimulation [98]. This is one of the few reported pleiotropic effects of statins that does not involve the inhibition of small GTPases.…”

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

“…A novel way in which statins may regulate leukocyte-endothelial adhesion is by directly binding to a novel regulatory site, the L-site (named for lovastatin), on the integrin LFA-1 found on leukocytes (50). LFA-1, a ␤2 integrin, is critical in the development of inflammatory arthritis in the K/BxN serum transfer mouse model of arthritis.…”