Blood monocytes infiltrate into the sites of inflammation and play major roles in host defense. Although the mechanisms of monocyte infiltration have not been fully understood, locally produced monocyte chemoattractants appear to be responsible for the recruitment of blood monocytes into the sites of inflammatory reactions. Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC-subfamily of the chemokine family and attracts blood monocytes both in vitro and in vivo. MCP-1 mRNA or protein was detected at high level in the lesions of several diseases such as atherosclerosis, arthritis, idiopathic pulmonary fibrosis, and various tumors, strongly suggesting that MCP-1 plays a critical role in the recruitment of monocytes in these diseases and tumors. Although a wide variety of cells produce MCP-1 in vitro in response to various stimuli, infiltrating monocytes themselves are one of the major cell source of MCP-1 in vivo. The mechanisms of MCP-1 gene expression were previously studied in human malignant glioma cells and mouse fibroblasts. In human malignant glioma cells, the binding of Sp1 to the proximal GC box was critical for the basal level of human MCP-1 gene expression, whereas the binding of NF-kB dimers to one of NF-kB binding sites, A2 site, was critical for the enhancer activity after stimulation. The importance of the NF-kB binding to the distal region of the mouse MCP-1 gene was also reported by using mouse fibroblasts. This year, we investigated the mechanisms of the hMCP-1 gene transcription by using human monocytic cell line, THP-1 cells, and found that the binding of two NF-kB/Rel protein dimers, (p65)2 and c-rel/p65, to not only A2 site but also another NF-kB site (A1 site) was important for the transcription of this gene. Our findings will provide important information how the production of this molecule is regulated inside the cells. It has recently become evident that certain NF-kB/Rel protein dimers such as (p65)2 or c-rel/p65 specifically regulate the transcription of certain genes. Our findings clearly show that these NF- kB/Rel protein dimers play an important role in the regulation of hMCP-1 gene transcription.
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