Matrix metalloproteinase-1 produced by human CXCL12-stimulated natural killer cells

Seiji Goda, Hiroshi Inoue, Hisanori Umehara, Michihiko Miyaji, Yutaka Nagano, Nari Harakawa, Hisao Imai, Peter Lee, James B. Macarthy, Takashi Ikeo, Naochika Domae, Yoji Shimizu, Joji Iida

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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 α2β1 integrin on CXCL12-stimulated NK-cell surface. The binding of pro-MMP-1 with α2β1 integrin required activation of G1-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 G1-occupied 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.

Original languageEnglish (US)
Pages (from-to)445-458
Number of pages14
JournalAmerican Journal of Pathology
Issue number2
StatePublished - Aug 2006


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