In this study we demonstrate that the overexpression of CD147 enhances the release and the activation of MMPs (MMP-2 and MMP-9) and the invasive potential during the differentiation of monocyte THP-1 cells to macrophage cells. This is in accordance with our previous study in human hepatoma cells .
MMPs are a family of Zn2+-containing enzymes that cleave most of the components of extracellular matrix (ECM) and are involved in physiologic connective tissue remodeling and in pathologic tissue destruction. MMPs can be regulated by different factors. Popp et al reported that calpain/calpastatin system mediated MMP-mRNA expression of the leukemic THP-1 cells and, as a result, their invasiveness . Worley et al identified that PPARγ and RXR agonists had complex effects on monocyte MMPs expression . In our present study, we employed CD147 to promote MMPs.
CD147 is a highly glycosylated transmembrane protein belonging to the immunoglobulin superfamily with two Ig domains. Previous studies have clearly demonstrated that CD147 is highly expressed on some tumor cells and is responsible for stimulating MMP production by stromal cells and/or other tumor cells, thereby leading to extracellular matrix degradation and elevated tumor growth and metastasis [21, 22]. CD147 has also been found to stimulate the secretion and the activation of MMPs, which are associated with tissue degradation and remodeling during inflammatory damage and wound healing. The up-regulation of the expression of CD147 in the synovial membrane of rheumatoid arthritis (RA) patients has been reported [23, 24]. Our recent studies have demonstrated that CD147 is highly expressed on monocytes in circulating blood and synovial fluid, and on macrophages/macrophages-like synovial cells in synovium from RA patients . Similarly, the up-regulation of the expression of CD147 on monocytes/macrophages may induce MMPs produced by fibroblasts and other monocytes/macrophages, and this process may play an essential role in articular cartilage lesion development in RA.
To explore the association of CD147 with the secretion and activation of MMPs, especially those in the cellular maturation, in our present study, human THP-1 monocytic cells were further stimulated to differentiate into a macrophage-like stage and some specific morphological and phenotypic alterations of PMA-treated THP-1 cells were detected. The high expression level of CD147 was observed in the differentiated process. Zymography, RT-PCR and ELISA results showed that the secretion and activation of MMP-2 and MMP-9 were significantly enhanced in the differentiated THP-1 cells. MMP-9 mRNA expression significantly increased in the differentiated THP-1 cells. Our results agree with the reports that the stimulation of the cells by PMA significantly augmented the release of MMP-9 [19, 20].
In view of the fact that CD147 may be required for the expression of gelatinases MMP-2 and MMP-9 and that the gelatinases MMP-2 and MMP-9 are expressed in leukemic cells [19, 20, 26], our study focused on the potential interaction between CD147 and MMPs, MMP-2 and MMP-9, in the differentiation process of monocytes into macrophages and in the invasion of monocytes/macrophages. We found that the overexpression of CD147 induced elevated levels of proMMP-2, pro-MMP-9 and their activated forms in differentiated THP-1 cells and the elevated levels of MMPs in turn enhanced the invasive ability of THP-1 cells. But the elevated expression and activation of MMPs and the enhanced invasive ability of THP-1 cells were blocked when HAb18G/CD147 antigonistic peptide AP-9 was added. These findings indicate that CD147 is involved in promoting the expression and activation of MMPs, which in turn increases the invasive potential of THP-1 cells.