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Published online before print March 30, 2005

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(Journal of Leukocyte Biology. 2005;78:259-265.)
© 2005 by Society for Leukocyte Biology

Production of matrix metalloproteinase-9 by activated human monocytes involves a phosphatidylinositol-3 kinase/Akt/IKK/NF-B pathway

Immunopathology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland

¹ Correspondence: Immunopathology Section, 30 Convent Drive, Building 30, Room 3A-300, NIDCR/NIH, Bethesda, MD 20892-4352. E-mail: lwahl{at}dir.nidcr.nih.gov

Matrix metalloproteinase-9 (MMP-9) is considered to be an important component in the progression of inflammation. Monocytes/macrophages are prominent at inflammation sites, and activation of these cells by stimulants, such as lipopolysaccharide (LPS) or tumor necrosis factor and granulocyte macrophage-colony stimulating factor, leads to the production of significant amounts of MMP-9. Here, we show that LPS stimulation of monocytes results in MMP-9 production through a phosphatidylinositol-3 kinase (PI-3K)/Akt/inhibitor of B (IB) kinase- (IKK)/nuclear factor (NF)-B pathway. This new role for Akt in signaling leading to MMP-9 production was demonstrated by inhibitor and immunoprecipitation studies. LY294002 or wortmannin, inhibitors of PI-3K, suppressed LPS-induced Akt activity and MMP-9 production. Evidence for the participation of Akt in monocyte MMP-9 synthesis was demonstrated by the inhibition of MMP-9 by SH-5, a specific inhibitor of Akt. The mechanism by which Akt regulates MMP-9 is through the activation of NF-B, as shown by coimmunoprecipitation of the phosphorylated form of IKK and Akt as well as the SH-5 suppression of the dissociation of IB from NF-B and the activation of NF-B p65. The role of NF-B in regulation of MMP-9 was demonstrated further by the inhibition of MMP-9 production by proteasome inhibitors, lactacystin and MG-132, which prevented the ubiquitination and dissociation of IB from NF-B. This is the first demonstration that Akt is involved in the signaling pathway leading to the production of monocyte MMP-9 and provides an additional approach in the regulation of this enzyme in human primary monocytes.

Key Words: lipopolysaccharide • pleckstrin homology • PIP3

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