An anti-inflammatory drug, propagermanium, may target GPI-anchored proteins associated with an MCP-1 receptor, CCR2.
Monocyte chemoattractant protein-1 (MCP-1) promotes the migration and activation of monocytes and plays a pivotal role in the development of chronic inflammation. Propagermanium (3-oxygermylpropionic acid polymer) has been used as a therapeutic agent against chronic hepatitis B in Japan. We report here that propagermanium specifically inhibits in vitro chemotactic migration of monocytes by MCP-1. Propagermanium did not inhibit binding of MCP-1 to a human monocytic cell line, THP-1 cells, or affect intracellular Ca(2+) mobilization or the cAMP concentration in MCP-1-treated THP-1 cells. The effect of propagermanium seems to require glycosylphosphatidylinositol (GPI)-anchored proteins, as cleavage of GPI anchors by phosphatidylinositol-phospholipase C (PI-PLC) eliminated the inhibitory activity of propagermanium. Anti-GPI-anchored protein antibodies, such as anti-CD55 and anti-CD59, reduced staining of C-C chemokine receptor 2 (CCR2) with an anti-CCR2 antibody against the N-terminus of CCR2 in a flow cytometric analysis, and these antibodies also selectively inhibited MCP-1-induced migration of THP-1 cells. Furthermore, under fluorescence microscopy, GPI-anchored proteins colocalized with CCR2 on THP-1 cells. These results suggest that propagermanium may target GPI-anchored proteins that are closely associated with CCR2 to selectively inhibit the MCP-1-induced chemotaxis, thus providing a mechanistic basis for the anti-inflammatory effects of the drug.
Yokochi
S
S
Central Research Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., Hokusei-cho, Inabe-gun, Mie 511-0406, Japan.
Hashimoto
H
H
Ishiwata
Y
Y
Shimokawa
H
H
Haino
M
M
Terashima
Y
Y
Matsushima
K
K
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001665:Binding Sites; D018958:CD55 Antigens / Q000378:metabolism; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005857:Germanium; D006023:Glycoproteins / Q000378:metabolism*; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D016167:Integrin alphaXbeta2 / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D011422:Propionates; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000737:chemistry / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C515334:CCR2 protein, human; D018958:CD55 Antigens; D006023:Glycoproteins; D017261:Glycosylphosphatidylinositols; D016167:Integrin alphaXbeta2; D009942:Organometallic Compounds; D011422:Propionates; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D005857:Germanium; C066750:propagermanium