Action profiles of statins and calcineurin inhibitors during human mixed lymphocyte reaction.
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)-gamma 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-gamma 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.
Takahashi
Hideo Kohka
HK
Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Iwagaki
Hiromi
H
Yagi
Takahito
T
Kanke
Toru
T
Liu
Keyue
K
Yoshino
Tadashi
T
Tanaka
Noriaki
N
Nishibori
Masahiro
M
D019013:CD40 Antigens / Q000378:metabolism; D065095:Calcineurin Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D020382:Interleukin-18 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008798:Mevalonic Acid / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology
D019013:CD40 Antigens; D065095:Calcineurin Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D007211:Indoles; D020382:Interleukin-18; C494439:LFA 878; C430123:LFA703; D009281:Naphthalenes; D010078:Oxazines; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D000077340:Fluvastatin; D007371:Interferon-gamma; D016572:Cyclosporine; D006903:Hydroxymethylglutaryl CoA Reductases; D017035:Pravastatin; D008798:Mevalonic Acid; D016559:Tacrolimus