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Chemokines are able to attract and activate leukocyte subsets in exclusion to other subsets (1) and monocyte chemoattractant protein 1 (MCP-1) is an inflammatory chemokine that targets monocytes, T lymphocytes and cells that express the C-C chemokine receptor (2) including myocytes (3). MCP-1 (also known as CCL2) was the third chemokine to be purified to homogeneity, after platelet factor 4 and interleukin 8 (4). It was discovered by a number of groups at similar times. One group was investigating factors involved in atherosclerosis (5), whilst another was assessing the properties of monocytes (6). The full structure was cloned by Yoshimura and colleagues (7).
In addition to its effects on leukocytes MCP-1 has profound effects on the innate and adaptive immune responses, due to it’s responsibility for monocyte recruitment (4).
This account outlines the origins and functions of MCP-1 before going on to discuss its relevance to inflammatory processes, including some of the research into methods of minimising the damage caused by inflammatory diseases by targeting either MCP-1 or its receptor.
Structure and origins of MCP-1
MCP-1 is a 76 amino acid protein and a member of the C-C family of chemokines (8), initially cloned by 3 separate groups in the late 1980s (1). Chemokines are chemotactic cytokines that are structurally related small proteins that have a role in leukocyte migration and activation (9). The C-C family are those in which 2 cysteine residues are adjacent, as opposed to the C-x-C family, in which they are separated by an amino acid (1). MCP-1 forms dimers at physiological concentrations (10) and it attracts monocytes in vitro at subnanomolar concentrations (11). Chemokines recruit cells by binding to their G-protein coupled receptors, but it isn’t a simple case of 1 receptor = 1 ligand (12) as different chemokines are able to act on multiple receptors, as well as individual receptors being activated by different ligands.
MCP-1 can be synthesised by mesangial and tubular epithelial cells (13) as well as the monocytes and other leukocytes. The synthesis of MCP-1 by mesangial cells has been shown to occur in response to glomerular injury and the factors involved in that process, such as interleukin-1, TNFα and low-density lipoprotein (13). In addition high glucose levels are also known to induce MCP-1, which has a relevance when discussing the role of MCP-1 in diseases such as diabetes (see below).
MCPs attract cells through the activation of their CCR2 receptor, expressed on the cell surface of monocytes (14). CCR2 can be expressed by non leukocytes including neurons, suggesting that it has a role in activities in addition to inflammation (4). CCR2 is expressed by virtually all monocytes but also around 15% of CD4+ T cells in the circulation (15). This is important when considering the involvement of MCP-1 in the adaptive and innate immune response. CCR2 is a member of the g protein coupled 7 transmembrane receptor superfamily expressed on most monocytes (9). The crucial role of the CCR2 receptor is evidenced by the fact that genetically deficient mice have reduced tissue recruitment of monocytes (14). Likewise mice lacking MCP-1 itself show similar deficits.
At physiological concentrations all free MCP-1 is monomeric and it is thought that it is this form of MCP-1, rather than the tetrameric form, that activates CCR2 (4). However there is currently debate about that, as other researchers believe that the dimmers are physiologically active (10).
Protein kinase C (PKC) activation is able to induce MCP-1 expression and macrophage recruitment (13). This forms another potential target for pharmacological intervention in disease processes, as altering the PKC activity can also influence MCP-1 expression, as described below.
MCP-1 in disease processes
Whilst ordinarily MCP-1 has a physiological action, the presence of inflammation gives rise to its up-regulation, and possibly pathological consequences. The normal physiological role of MCP-1 does involve the recruitment of monocytes, which are involved in cardiac repair and protection processes (16). Of particular interest is the fact that MCP-1 is chemotactic for endothelial cells and can induce those cells to sprout, as well as encouraging the growth of collateral vessels through ischaemic tissue (16). Thus chemokines, whilst potentially damaging to cardiac tissue, are also important in early cardiac repair. CCR2 knockout mice had a reduced amount of cardiac fibrosis following myocardial infarct, indicating that, as macrophage infiltration had been reduced, myocardial ischaemia-reperfusion injury was also reduced (3).
MCP-1 has been found to be up-regulated in a number of disease processes, including pancreatitis, where it is believed to contribute to the pathogenesis of mononuclear infiltration (2). MCP-1 is produced in pathological settings that are characterised by monocyte-rich infiltrates, including tuberculosis and atherosclerosis (1). Inflammatory diseases are often characterised by MCP-1 expression, such that rheumatoid arthritis inflamed synovium has an up-regulated MCP-1 expression and anti-arthritic drugs act to reduce the levels (9). Irritable bowel disease involves inflammatory chemokines in the mucosa. The mere presence of MCP-1 is believed to be responsible for the invasion of blood monocytes and granulocytes in the inflamed tissue (17). This was evidenced by the fact that blockade of the effect of MCP-1 via a neutralising antibody abrogated the recruitment of monocytes and that mRNA is upregulated, as is the protein itself. MCP-1 mRNA and protein has been shown to be strongly expressed in epithelial and endothelial cells from patients with idiopathic pulmonary fibrosis (IPF), a chronic fibrosing interstitial pneumonia with a median life expectancy of 3-4 years (10).
Chronic pancreatitis is characterised by the inflammatory infiltration of pancreatic tissue, as well as fibrosis and atrophy of the acinar cells (8). Figure 2 below gives a summary of the chemokines and disease process for pancreatitis. In particular it should be noted that MCP-1 was induced by injured acinar and ductal cells and damaged tissue as well as the expected monocytes and macrophages (8).
MCP-1 is involved in atherosclerosis as the early stages of the disease involve the infiltration of circulating monocytes to the arterial subendothelium (4). In human atherosclerosis it has been found that MCP-1 is synthesised primarily by endothelial cells but also subendothelial macrophages and foam cells (1). Atherosclerosis develops from the migration of monocytes through the vascular walls, whereupon they are changed to lipid-laden foam cells (18). The expression of MCP-1 is directly related to the extent of atherosclerosis and macrophage infiltration, such that it is considered a biochemical marker of early atherosclerosis. Mature atherosclerotic plaques also produce MCP-1 from subendothelial macrophages. Indeed all elements of the arterial wall are capable of synthesising MCP-1 (4). MCP-1 deficient mice could be fed a high cholesterol diet and not develop atherosclerosis, in conjunction with a decreased number of macrophages being present in the arterial wall (4).
The involvement of MCP-1 in diabetes mellitus has also been indicated, whereby the serum concentrations of MCP-1 were shown to be significantly higher in diabetes mellitus patients, when compared to healthy controls (18). Likewise the expression of CCR2 on monocytes was also significantly increased, indicating that monocyte accumulation in diabetic vascular disease is a result of over production of MCP-1 and an up-regulation of CCR2 leading to monocytes extravasation.
MCP-1 is also involved in diseases characterised by disruption of the blood brain barrier leading to vascular permeability and leukocyte infiltration, including stroke, multiple sclerosis and Alzheimer’s disease (19). MCP-1 knockout mice have been shown to have reduced levels of inflammatory cytokines as well as reduced ischaemia and leukocyte infiltration (20). During CNS inflammation MCP-1 is expressed in perivascular space as well as brain parenchyma (19). Further it has been shown that MCP-1 is actually directly responsible for increasing blood brain barrier permeability, achieving this by altering the tight junction complex (19). MCP-1 also acts indirectly by recruiting monocytes into the brain parenchyma, which will also act to increase blood brain barrier permeability.
It is worth noting that, in a rather contrary way, MCP-1 is actually reduced in multiple sclerosis cerebrospinal fluid, and it is suggested that this is due to it being consumed by CCR2+ migrating cells (15). MCP-1 is therefore produced by reactive astrocytes during inflammation, has a role in leukocyte accumulation in multiple sclerosis lesions and is then consumed by the CCR2+ cells as they enter the lesion (15).
Pharmacological targets of MCP-1
The inflammatory aspects of pancreatitis are mediated in the main part by monocytes and macrophages (8), so any factors that increase their recruitment would be suitable targets for the treatment of chronic pancreatitis. Gene therapy has been used in the treatment of pancreatitis, whereby an amino terminal deletion of MCP-1 causes a mutated form that acts as a potent dominant negative MCP-1 agonist (mMCP-1) (8). When this mMCP-1 was used in a rat model of pancreatitis there was significantly less pancreatic inflammation than when an empty plasmid was used. This can be seen in figure 3 below, where B is a rat which shows signs of inflammatory pancreatitis, and C is a rat treated with mMCP-1 and shows much less inflammation. The authors conclusions were that mMCP-1 gene transfer resulted in the suppression of monocyte and macrophage recruitment and activation (8).
The 7ND (amino terminal deletion) model of MCP-1 forms heterodimers with wild type MCP-1 and prevents wild type MCP-1 from binding to CCR2 receptors (10). 7ND gene transfer was found to greatly reduce the pathological effects in a mouse model of IPF (bleomycin induced pneumopathy). Specifically it acted to attenuate DNA damage, apoptosis and pulmonary fibrosis if given 7 days after the initial insult. The authors concluded therefore that MCP-1 has its principal role in IPF during the late phases of lung injury and fibrogenesis and has a much lesser role in the early inflammatory stages (10).
The use of LY333531, a protein kinase C inhibitor, has been shown to reduce the expression of MCP-1 in the kidney (13), indicating that PKC is necessary for the synthesis and expression of MCP-1, and anti-inflammatory effects can be mediated by it’s blockade. This has much potential for future therapy as it wouldn’t affect the other ligands binding to CCR2, thus shouldn’t have as great an impact on physiological activity.
MCP-1 is a potent chemokine that has a crucial role in the recruitment and activation of monocytes in the inflammatory and immune responses. Unfortunately it has been strongly implicated in a number of pathological conditions characterised by inflammation including atherosclerosis, rheumatoid arthritis and diabetes mellitus. Therefore pharmacological targets aim to reduce its overall expression or reduce the activation of its CCR2 receptor. Unfortunately it is not possible to simply block CCR2 as it has too many necessary physiological roles. Early CCR2 antagonists suffered from poor binding, poor functional activity and off-target activities (9) which diminished the enthusiasm for the development of a pharmacological therapy targeting CCR2. However research does continue and there is little argument that over expression of MCP-1 does have a significant role in inflammatory disease. The task ahead is to investigate why and try to alter the hyperactivity in a way that reduces pathological symptoms at the same time as retained physiological activity.
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