Inhibitory influences of xanthine oxidase inhibitor and angiotensin I-converting enzyme inhibitor on multinucleated giant cell formation from monocytes by downregulation of adhesion molecules and purinergic receptors

Abstract

Background: Allopurinol, a xanthine oxidase inhibitor, and captopril, an inhibitor of angiotensin I-converting enzyme, are widely used for hyperuricaemia and hypertension, respectively. There have been reported cases showing that these two agents are effective for the treatment of granulomatous diseases such as sarcoidosis, although the mode of action is not elucidated. Objectives: We examined the in vitro effects of these agents on the formation of multinucleated giant cells (MGC) from human monocytes by concanavalin A-stimulated mononuclear cell supernatants (conditioned medium). Methods: We cultured monocytes with conditioned medium and each agent and compared the rate of MGC formation as well as the expression of adhesion molecules and P2X 7 receptor, which are involved in MGC formation. Results: The addition of 25 or 100 μg mL-1 allopurinol or 0.125-1.0 μg mL-1 captopril inhibited MGC formation. Monocytes treated with these agents exhibited less expression of intercellular adhesion molecular-1 (ICAM-1) than untreated monocytes. The susceptibility of monocytes cultured in conditioned medium for 24 h to 2′-and 3′-o-(4-benzoyl-benzoyl) adenosine triphosphate-mediated cytolysis was significantly lower in monocytes treated with these agents than in untreated monocytes. Conclusions: Allopurinol and captopril have a therapeutic effect on granulomatous disorders by a direct action on monocyte/macrophage lineage cells partly through downregulation of ICAM-1 and P2X7 receptor.