Expression of MCP-1 is ubiquitous in various cell types and is upregulated by a wide variety of stimuli. The list of MCP-1-producing cell types grew rapidly after the aforementioned pioneer studies in 1989 [13
]. A summary of MCP-1-producing cell types and stimuli can be found in in a review by Van Collie et al. [8
]. In addition, adipocytes have been recognized as an important source of MCP-1[19
Treatments that have been reported to inhibit MCP-1 over-production and improve diabetic nephropathy conditions.
Human MCP-1 gene consists of 3 exons of 145, 118 and 478 bp in length, and 2 introns of 800 and 385 bp in length. In 1990 Shyy et al. reported two phorbol ester responsive elements (TRE) 129 and 157 bp upstream from the translation initiation site, and the upregulation of MCP-1 expression in cultured endothelial cell after phorbol ester treatment [21
]. Subsequently Ueda et al. [22
] identified two remote kappa B binding sites known as A1 (−2640/−2632) and A2 (−2612/−2603). A2 was found to be important for enhancer activity induced by IL-1β, TNF-α, and 2-O-tetradecanoylphorbol 13-acetate (TPA). One GC box (−64/−59) was also found important for the maintenance of basal transcriptional activity, and can possibly be controlled by Sp1. A graphical summary of the transcriptional regulatory elements of human MCP-1 gene is shown in . Further studies by Ueda et al. [23
] revealed that lipopolysaccharide (LPS) stimulation induces the binding of p65/p65, c-Rel/p65, p50/p65, and p50/cRel to the A2 probe and increase of MCP-1 mRNA in human acute monocytic leukemia THP-1 cells, while TPA treatment on this cell line only resulted in the binding of p65/p50 to A2 probe, but not increase of MCP-1 mRNA. However, TPA treatment on other human cell lines such as cervical carcinoma HeLa, osteosarcoma HOS, and glioblastoma A172 cells induced both binding of p65/p65 and cRel/p65 to A2 probe, and elevated MCP-1 mRNA levels. Co-transfection of p65 or p65/cRel with hMCP-1 showed trans-activation. Thus stimulus-specific and tissue-specific regulation on human MCP-1 gene has been emphasized [22
A graphical summary of the transcriptional regulatory elements in human MCP-1 gene. TRE, phorbol ester responsive elements. The numbers indicate length in base pair. The schematic illustration is not proportional to the length of the DNA.
In rat JE gene, the −141/−88 promoter region is reportedly responsive to the phorbol ester TPA, and the −70/−38 promoter region is essential for basal activity. The later region harbors the sequence TGACTCC, resembling the consensus site for AP-1 binding TGACTCA. The JE AP-1 site and the consensus AP-1 site have an overlapping but not identical binding spectrum for AP-1 proteins [24
]. Hanazawa et al. reported that TNF-α induces JE expression via c-fos and c-jun genes following protein kinase C activation in mouse osteoblastic MC3T3-E1 cells, and curcumin, a specific inhibitor of c-jun/AP-1, markedly inhibited JE gene expression induced by the cytokine [25
]. Ping et al. further reported that TNF regulates the occupancy of both distal and proximal regulatory regions of murine JE gene, and demonstrated a multi-step model involving chromatin accessibility, transcription factor complex assembly, and protein phosphorylation [26
]. In a subsequent report from Ping et al. [27
] it was shown that two distal kappa B sites, a novel dimethylsulfate-hypersensitive sequence, and a promoter proximal Sp1 site were required for TNF induction, and illustrated a crucial role of p65 in the assembly of a NFκB dependent enhancer in vivo.
The regulation of MCP-1 gene expression in pancreatic islets has been extensively studied due to its clinical relevance (refer to Section 7). Reported regulatory factors include primary inflammatory cytokines (i.e. IL-1β, TNFα), lipopolysaccharide, ERK1/2 and p38 MAPK, but not glucose or nitric oxide [28
]. An IL-1β-responsive enhancer region has been identified between −2180 bp and −2478 bp of the MCP-1 gene in rat β-cells, which contains two NF κB sites binding to p65/p50 heterodimers and p65 homodimer. Mutation of either NFκB sites present in this region abrogated IL-1 β-induced MCP-1 promoter activity. Therefore NFκB plays an important role for MCP-1 expression in β-cells [30
]. The lack of expression of the transcriptional repressor B-cell lymphoma-6 (BCL-6), which inhibits MCP-1 gene expression and NF κB activity, may render β cells particularly susceptible to propagating inflammation [31
]. The primary cytokines reportedly induce the expression of I κB isoforms and MCP-1 several fold higher in rat INS-1E cells than in fibroblasts 208F cells, and correlate with a proapoptotic outcome [32
]. Angiotensin II (AngII) is another factor regulating the expression of MCP-1 in rat RINm5F β-cell line and activating MCP-1 promoter, possibly through a MAPK signaling mechanism [33
Role of hypoxia in MCP-1 expression in brain, cardiovascular system, and adipocytes has been reported. Human MCP-1 was found regulated by hypoxia-inducible factor −1 (HIF-1) in astrocytes [34
], and upregulation of MCP-1 expression in neurons induced by hypoxic preconditioning protected mice from stroke [35
]. Chronic intermittent hypoxia also upregulated MCP-1 expression in the carotid body in rats [36
]. Controversial results were documented regarding the responses of adipocytes to hypoxic condition. For example, Yu et al. [37
] showed upregulation of MCP-1 mRNA and protein expression in mouse 3T3-L1 adipocytes under 1% O2
atmosphere. In contrast, Famulla et al. [38
] reported that the same hypoxic condition reduced the secretion of MCP-1 from human primary adipocytes.
Other than transcriptional regulation, glucocorticoids have been reported to trigger the specific binding of glucocorticoid receptor to MCP-1 mRNA, facilitating the mRNA degradation [39
]. Multiple studies have reported parallel increases of mRNA, protein, and monocyte chemotactic activity of MCP-1 [14