The Cannabinoid Receptor CB2 Exerts Antifibrotic Effects in Experimental Dermal Fibrosis

被引:101
作者
Akhmetshina, Alfiya
Dees, Clara
Busch, Nicole
Beer, Juergen
Sarter, Kerstin
Zwerina, Jochen
Zimmer, Andreas [2 ]
Distler, Oliver [3 ]
Schett, Georg
Distler, Joerg H. W. [1 ]
机构
[1] Univ Erlangen Nurnberg, Dept Internal Med 3, D-91054 Erlangen, Germany
[2] Univ Bonn, D-5300 Bonn, Germany
[3] Univ Zurich Hosp, CH-8091 Zurich, Switzerland
来源
ARTHRITIS AND RHEUMATISM | 2009年 / 60卷 / 04期
关键词
SYSTEMIC-SCLEROSIS; FIBROBLASTS; EXPRESSION; CELLS;
D O I
10.1002/art.24395
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. The cannabinoid receptor CB2 is predominantly expressed in non-neuronal tissue and exerts potent immunomodulatory effects. This study was undertaken to evaluate the role of CB2 in the pathogenesis of dermal fibrosis. Methods. Mice deficient in CB2 (CB2(-/-) mice) and their wild-type littermates (CB2(+/+) mice) were injected with bleomycin to induce experimental fibrosis. Mice were treated with selective agonists and antagonists of CB2. Lesional skin was evaluated for dermal thickness and numbers of infiltrating leukocytes. Bone marrow transplantation experiments were performed. Results. CB2(-/-) mice were more sensitive to bleomycin-induced dermal fibrosis than were CB2(+/+) mice, and showed increased dermal thickness. Leukocyte counts were significantly higher in the lesional skin of CB2(+/+) mice. Increased dermal fibrosis was also observed upon treatment with the CB2 antagonist AM-630. In contrast, the selective CB2 agonist JWH-133 reduced leukocyte infiltration and dermal thickening. The phenotype of CB2(-/-) mice was mimicked by transplantation of CB2(-/-) bone marrow into CB2(+/+) mice, whereas CB2(-/-) mice transplanted with bone marrow from CB2(+/+) mice did not display an increased sensitivity to bleomycin-induced fibrosis, indicating that leukocyte expression of CB2 critically influences experimental fibrosis. Conclusion. Our findings indicate that CB2 limits leukocyte infiltration and tissue fibrosis in experimental dermal fibrosis. Since selective CB2 agonists are available and well tolerated, CB2 might be an interesting molecular target for the treatment of early inflammatory stages of systemic sclerosis.
引用
收藏
页码:1129 / 1136
页数:8
相关论文
共 19 条
[1]   Treatment With Imatinib Prevents Fibrosis in Different Preclinical Models of Systemic Sclerosis and Induces Regression of Established Fibrosis [J].
Akhmetshina, Alfiva ;
Venalis, Paulius ;
Dees, Clara ;
Busch, Nicole ;
Zwerina, Jochen ;
Schett, Georg ;
Distler, Oliver ;
Distler, Joerg H. W. .
ARTHRITIS AND RHEUMATISM, 2009, 60 (01) :219-224
[2]   Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis [J].
Akhmetshina, Alfiya ;
Dees, Clara ;
Pileckyte, Margarita ;
Maurer, Britta ;
Axmann, Roland ;
Juengel, Astrid ;
Zwerina, Jochen ;
Gay, Steffen ;
Schett, Georg ;
Distler, Oliver ;
Distler, Joerg H. W. .
FASEB JOURNAL, 2008, 22 (07) :2214-2222
[3]   Cannabinoid receptors as novel targets for the treatment of melanoma [J].
Blazquez, Cristina ;
Carracedo, Arkaitz ;
Barrado, Lucia ;
Jose Real, Pedro ;
Fernandez-Luna, Jose Luis ;
Velasco, Guillermo ;
Malumbres, Marcos ;
Guzman, Manuel .
FASEB JOURNAL, 2006, 20 (14) :2633-+
[4]   Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB2 receptor [J].
Buckley , NE ;
McCoy, KL ;
Mezey, É ;
Bonner, T ;
Zimmer, A ;
Felder, CC ;
Glass, M ;
Zimmer, A .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2000, 396 (2-3) :141-149
[5]   Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts - Evidence for autocrine regulation of myofibroblast differentiation [J].
Carulli, MT ;
Ong, VH ;
Ponticos, M ;
Xu, SW ;
Abraham, DJ ;
Black, CM ;
Denton, CP .
ARTHRITIS AND RHEUMATISM, 2005, 52 (12) :3772-3782
[6]  
DISTLER JH, 2008, RHEUMATOLOGY OXFORD
[7]   Monocyte chemoattractant protein 1 released from glycosaminoglycans mediates its profibrotic effects in systemic sclerosis via the release of interleukin-4 from T cells [J].
Distler, JHW ;
Jüngel, A ;
Caretto, D ;
Schulze-Horsel, U ;
Kowal-Bielecka, O ;
Gay, RE ;
Michel, BA ;
Müller-Ladner, U ;
Kalden, JR ;
Gay, S ;
Distler, O .
ARTHRITIS AND RHEUMATISM, 2006, 54 (01) :214-225
[8]   Antifibrogenic role of the cannabinoid receptor CB2 in the liver [J].
Julien, B ;
Grenard, P ;
Teixeira-Clerc, F ;
Van Nhieu, JT ;
Li, LY ;
Karsak, M ;
Zimmer, A ;
Mallat, A ;
Lotersztajn, S .
GASTROENTEROLOGY, 2005, 128 (03) :742-755
[9]   IDENTIFICATION OF FIBROBLASTS RESPONSIBLE FOR INCREASED COLLAGEN PRODUCTION IN LOCALIZED SCLERODERMA BY INSITU HYBRIDIZATION [J].
KAHARI, VM ;
SANDBERG, M ;
KALIMO, H ;
VUORIO, T ;
VUORIO, E .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1988, 90 (05) :664-670
[10]   Attenuation of allergic contact dermatitis through the endocannabinoid system [J].
Karsak, Meliha ;
Gaffal, Evelyn ;
Date, Rahul ;
Wang-Eckhardt, Lihua ;
Rehnelt, Jennifer ;
Petrosino, Stefania ;
Starowicz, Katarzyna ;
Steuder, Regina ;
Schlicker, Eberhard ;
Cravatt, Benjamin ;
Mechoulam, Raphael ;
Buettner, Reinhard ;
Werner, Sabine ;
Di Marzo, Vincenzo ;
Tueting, Thomas ;
Zimmer, Andreas .
SCIENCE, 2007, 316 (5830) :1494-1497