Action profiles of statins and calcineurin inhibitors during human mixed lymphocyte reaction

• Published in: Clinical Immunology Vol. 123; no. 3; pp. 324 - 332
• Main Authors: Takahashi, Hideo Kohka, Iwagaki, Hiromi, Yagi, Takahito, Kanke, Toru, Liu, Keyue, Yoshino, Tadashi, Tanaka, Noriaki, Nishibori, Masahiro
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.06.2007; Elsevier
• Subjects: Allergy and Immunology; Biological and medical sciences; Calcineurin Inhibitors; CD40 Antigens - metabolism; Cell Proliferation - drug effects; Cyclosporine - pharmacology; Fatty Acids, Monounsaturated - pharmacology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; IL-18; Immunosuppressive Agents - pharmacology; Indoles - pharmacology; Intercellular Adhesion Molecule-1 - metabolism; Interferon-gamma - metabolism; Interleukin-12 - metabolism; Interleukin-18 - pharmacology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocyte Culture Test, Mixed; Medical sciences; Mevalonic Acid - pharmacology; Mixed lymphocyte reaction; Monocytes - drug effects; Monocytes - metabolism; Naphthalenes - pharmacology; Oxazines - pharmacology; Pravastatin - pharmacology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Statins; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tacrolimus - pharmacology; Mixed lymphocyte reaction; IL-18; Statins; Calcineurin inhibitors; Human; Immunopathology; Enzyme; Calcineurin; Cytokine; Enzyme inhibitor; Statin derivative; Interleukin 18; Medicine; Immunology; Hydroxymethylglutaryl-CoA reductase; Oxidoreductases; Antilipemic agent
• ISSN: 1521-6616; 1521-7035; 1365-2567
• DOI: 10.1016/j.clim.2007.02.003

Abstract The cell-to-cell interaction through binding intercellular adhesion molecule (ICAM)-1 and CD40 on monocytes and their ligands such as lymphocyte function-associated antigen (LFA)-1 and CD40 ligand (CD40L) on T-cells plays roles in cytokine production and T-cell proliferation. Interleukin (IL)-18, which is elevated in the plasma during acute rejection after organ transplantation, induces the expression of ICAM-1 and CD40 on monocytes, the production of interferon (IFN)-γ and IL-12 and the proliferation of T-cells during the human mixed lymphocyte reaction (MLR). In addition to the cholesterol lowering effect, statins improve patient survival and decrease rejection episodes in transplant recipients. In the present study, we investigated the difference of effect of statins and calcineurin inhibitors during MLR. 3-Hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, fluvastatin and pravastatin and statin-derived LFA-1 inhibitors, LFA703 and LFA878, which did not inhibit HMG-CoA reductase, suppressed the production of IFN-γ and IL-12 and the lymphocyte proliferation as well as the expression of ICAM-1 and CD40 on monocytes regardless of the presence of IL-18. However, the calcineurin inhibitors, tacrolimus and cyclosporine A (CsA), inhibited the IL-18-enhanced cytokine production and lymphocyte proliferation without any effect on the adhesion molecule expression. Thus, the action mechanism of stain is different from that of calcineurin inhibitors.