title: Clusterin stimulates the chemotactic migration of macrophages through a pertussis toxin sensitive G-protein-coupled receptor and Gβγ-dependent pathways.
abstract: Clusterin induces the expression of various chemotactic cytokines including tumor necrosis factor-α (TNF-α) in macrophages and is involved in the cell migration. According to the results of this study, clusterin induced the directional migration (chemotaxis) of macrophages based on a checkerboard analysis. The chemotactic activity of clusterin was prevented by pretreatment with pertussis toxin (PTX), indicating that the Gαi/o-protein coupled receptor (GPCR) was involved in the chemotactic response of clusterin. Clusterin-stimulated chemotaxis was abrogated in a dose-dependent manner by pretreatment with gallein (a Gβγ inhibitor), indicating the involvement of Gβγ released from the GPCR. In addition, inhibitors of phospholipase C (PLC, U73122) and phosphoinositide 3-kinase (PI3K, LY294002), the key targets of Gβγ binding and activation, suppressed chemotactic migration by clusterin. The phosphorylation of Akt induced by clusterin was blocked by pretreatment with gallein or LY294002 but not with U73122, indicating that Gβγ released from the PTX-sensitive Gi protein complex activated PLC and PI3K/Akt signaling pathways separately. The activation of cellular MAP kinases was essential in that their inhibitors blocked clusterin-induced chemotaxis, and Gβγ was required for the activation of MAP kinases because gallein reduced their phosphorylations induced by clusterin. In addition, the inflammation-induced migration of macrophages was greatly reduced in clusterin-deficient mice based on a thioglycollate-induced peritonitis model system. These results suggest that clusterin stimulates the chemotactic migration of macrophages through a PTX-sensitive GPCR and Gβγ-dependent pathways and describe a novel role of clusterin as a chemoattractant of monocytes/macrophages, suggesting that clusterin may serve as a molecular bridge between inflammation and its remodeling of related tissue by recruiting immune cells.
authors.affiliation: Department of Pharmacology, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Byeong-Ho
authors.initials: BH
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Shim
authors.affiliation: Department of Pharmacology, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Yoo-Keung
authors.initials: YK
authors.lastname: Tae
authors.affiliation: Department of Pharmacology, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Song
authors.affiliation: Department of Internal Medicine, College of Medicine, Dongguk University Ilsan Hospital, Republic of Korea.
authors.forename: Byong-Kwan
authors.initials: BK
authors.lastname: Choi
authors.affiliation: Department of Anatomy, College of Medicine, Inha University, Republic of Korea.
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Park
authors.affiliation: Department of Pharmacology, College of Medicine, Korea University, Seoul, Republic of Korea. Electronic address: bhmin@korea.ac.kr.
authors.forename: Bon-Hong
authors.initials: BH
authors.lastname: Min
mesh_terms: D000818:Animals; D002633:Chemotaxis / Q000187:drug effects; D051152:Clusterin / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D051152:Clusterin; D020928:Mitogen-Activated Protein Kinases; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D010738:Type C Phospholipases
keywords: Chemotaxis; Clusterin; G-protein-coupled receptor; Macrophage; Pertussis toxin