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J. Biol. Chem., Vol. 281, Issue 18, 12908-12918, May 5, 2006

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Effects of Peripheral Cannabinoid Receptor Ligands on Motility and Polarization in Neutrophil-like HL60 Cells and Human Neutrophils^*

Rina Kurihara, Yumi Tohyama¹, Satoshi Matsusaka, Hiromu Naruse, Emi Kinoshita, Takayuki Tsujioka^¶, Yoshinao Katsumata, and Hirohei Yamamura

From the Division of Proteomics, Department of Genome Sciences, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, the Department of Legal Medicine and Bioethics, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan, and the ^¶Department of Laboratory Medicine and Clinical Pathology, Kawasaki Medical School, Kurashiki 701-0192, Japan

The possible role of the peripheral cannabinoid receptor (CB2) in neutrophil migration was investigated by using human promyelocytic HL60 cells differentiated into neutrophil-like cells and human neutrophils isolated from whole blood. Cell surface expression of CB2 on HL60 cells, on neutrophil-like HL60 cells, and on human neutrophils was confirmed by flow cytometry. Upon stimulation with either of the CB2 ligands JWH015 and 2-arachidonoylglycerol (2-AG), neutrophil-like HL60 cells rapidly extended and retracted one or more pseudopods containing F-actin in different directions instead of developing front/rear polarity typically exhibited by migrating leukocytes. Activity of the Rho-GTPase RhoA decreased in response to CB2 stimulation, whereas Rac1, Rac2, and Cdc42 activity increased. Moreover, treatment of cells with RhoA-dependent protein kinase (p160-ROCK) inhibitor Y27632 yielded cytoskeletal organization similar to that of CB2-stimulated cells. In human neutrophils, neither JWH015 nor 2-AG induced motility or morphologic alterations. However, pretreatment of neutrophils with these ligands disrupted N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced front/rear polarization and migration and also substantially suppressed fMLP-induced RhoA activity. These results suggest that CB2 might play a role in regulating excessive inflammatory response by controlling RhoA activation, thereby suppressing neutrophil migration.

Received for publication, October 5, 2005 , and in revised form, March 1, 2006.

^* This work was supported in part by a grant-in-aid for Scientific Research from the Japan Society for the Promotion of Science, the 21st Century COE Program of the Ministry of Education, and the Osaka Medical Research Foundation for Incurable Diseases. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed. Tel.: 81-78-382-5406; Fax: 81-78-382-5419; E-mail: ytohyama{at}med.kobe-u.ac.jp.

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