Matrix metalloproteinase-1 produced by human CXCL12-stimulated natural killer cells.
Natural killer (NK) cells play a key role in inflammation and tumor regression through their ability to migrate into tissues. CXCL12 is a chemokine that promotes lymphocyte invasion and migration into tissues; however, the mechanism for this process remains incompletely understood. In this study, we show that CXCL12 significantly enhanced CD16(+)CD56(+) human peripheral NK-cell invasion into type I collagen by the catalytic activity of matrix metalloproteinase-1 (MMP-1). Confocal immunofluorescence and co-immunoprecipitation studies suggest that MMP-1 colocalized with alpha(2)beta(1) integrin on CXCL-12-stimulated NK-cell surface. The binding of pro-MMP-1 with alpha(2)beta(1) integrin required activation of G(i)-coupled pathway. However, the production of MMP-1 from CXCL12-stimulated NK cells was mediated by p38 and mitogen-activated or extracellular signal-regulation protein kinase kinase 1/2 in a manner independent of the G(i)-coupled pathway. These results suggest that CXCL12/CXCR4 interaction transduces the two signaling pathways to promote NK-cell invasion, which stimulates pericellular degradation of extracellular matrix proteins by membrane-associated MMP-1. The mechanisms would thus play a role in facilitating lymphocyte trafficking and accumulation in tissues during physiological and pathological processes.
Goda
Seiji
S
Department of Biochemistry, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata-shi, Osaka 573-1121, Japan. goda@cc.osaka-dent.ac.jp
Inoue
Hiroshi
H
Umehara
Hisanori
H
Miyaji
Michihiko
M
Nagano
Yutaka
Y
Harakawa
Nari
N
Imai
Hisao
H
Lee
Peter
P
Macarthy
James B
JB
Ikeo
Takashi
T
Domae
Naochika
N
Shimizu
Yoji
Y
Iida
Joji
J
D019002:CD56 Antigen / Q000276:immunology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D024042:Collagen Type I / Q000378:metabolism; D017077:Culture Media, Conditioned; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D017452:Receptors, IgG / Q000276:immunology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D019002:CD56 Antigen; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D024042:Collagen Type I; D017077:Culture Media, Conditioned; D038982:Integrin alpha2beta1; D017452:Receptors, IgG; D019715:Tissue Inhibitor of Metalloproteinase-1; D037342:Pertussis Toxin; C482128:MAP2K2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020781:Matrix Metalloproteinase 1