A CCR1 antagonist prevents the development of experimental autoimmune myocarditis in association with T cell inactivation.
Chemokines play an important role in induction of chemotaxis of immune cells. CCR1 is a chemokine receptor expressed on neutrophils, monocytes, and T lymphocytes. The role of CCR1 in immunity is not well examined. We demonstrated the role of CCR1 on T lymphocytes and the effect of a CCR1 antagonist, BX471 in myocarditis. Lewis rats were immunized with cardiac myosin on day 0 to establish experimental autoimmune myocarditis. Rats were then administered BX471 subcutaneously every day (group BX0: n = 7) or from day 14 (group BX14: n = 7) and were killed on day 21. We confirmed expression of CCR1 in cells infiltrating the myocardium by immunohistochemistry and FACS analysis. The development of myocarditis was almost completely prevented in group BX0, and myocarditis-affected areas were significantly decreased in size in group BX14. Cardiac function was markedly improved. Ribonuclease protection assay showed that the CCR1 antagonist treatment suppressed mRNA expression for IL-6, IL-1beta, and TNF-alpha in the hearts. An antigen-specific T cell proliferation assay was performed with CD4-positive T cells isolated from control rats immunized with cardiac myosin. T cell proliferation was inhibited by the CCR1 antagonist. Additionally, we showed by Western blot that the CCR1 antagonist suppressed ERK1/2 and JNK activities in T cells stimulated with myosin and that IL-2 reversed this suppression. The CCR1 antagonist reduced the severity of EAM by inhibiting cytokine expression and inducing T cell inactivation. Thus, the CCR1 antagonist may provide a novel therapeutic strategy treatment of myocarditis.
Futamatsu
Hideki
H
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Suzuki
Jun-ichi
J
Koga
Noritaka
N
Adachi
Susumu
S
Kosuge
Hisanori
H
Maejima
Yasuhiro
Y
Haga
Takaaki
T
Hirao
Kenzo
K
Horuk
Richard
R
Isobe
Mitsuaki
M
D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control*; D001835:Body Weight; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics; D004452:Echocardiography; D000939:Epitopes / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D009205:Myocarditis / Q000517:prevention & control*; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013552:Swine
C515302:Ccr1 protein, rat; D016207:Cytokines; D000939:Epitopes; D007376:Interleukin-2; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases