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(American Journal of Pathology. 2006;169:445-458.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050676

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^** and Joji Iida^**

From the Departments of Biochemistry,^* Periodontology, Internal Medicine, and Physiology, Osaka Dental University, Osaka, Japan; the Division of Hematology and Immunology,^¶ Department of Internal Medicine, Kanazawa Medical University, Kahoku-gun, Ishikawa, Japan; and the Departments of Surgery,|| Laboratory Medicine and Pathology,^** Cancer Center, University of Minnesota, Minneapolis, Minnesota

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 ₂ß₁ integrin on CXCL-12-stimulated NK-cell surface. The binding of pro-MMP-1 with ₂ß₁ 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.

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