CCL2

For the ICAO airport code see is_associated_with::Candle Lake Airpark, for the diradical compound see is_associated_with::Dichlorocarbene.

The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemotactic protein 1 (MCP1) and small inducible cytokine A2. CCL2 is a small is_associated_with::cytokine that belongs to the CC is_associated_with::chemokine family. CCL2 recruits is_associated_with::monocytes, is_associated_with::memory T cells, and is_associated_with::dendritic cells to the sites of is_associated_with::inflammation produced by either tissue injury or is_associated_with::infection.

Genomics
In the human genome, CCL2 and many other CC chemokines are located on is_associated_with::chromosome 17 (17q11.2-q21.1). The gene span is 1,927 bases and the CCL2 gene resides on the Watson (plus) strand. The CCL2 gene has three is_associated_with::exons and two is_associated_with::introns. The CCL2 is_associated_with::protein precursor contains a signal peptide of 23 is_associated_with::amino acids. In turn, the mature CCL2 is 76 amino acids long. The CCL2 predicted weight is 11.025 kiloDaltons (kDa).

The gene homologous to CCL2 in the mouse is Sig-je.

Population genetics
In humans, the levels of CCL2 can vary considerably. In the white people of European descent, the multivariable-adjusted heritability of CCL2 concentrations is as much as 0.37 in the blood plasma and 0.44 - in the serum

Molecular biology
CCL2 is a monomeric is_associated_with::polypeptide, with a is_associated_with::molecular weight of approximately 13 kDa. CCL2 is anchored in the plasma membrane of endothelial cells by glycosaminoglycan side chains of proteoglycans. CCL2 is primarily secreted by is_associated_with::monocytes, is_associated_with::macrophages and is_associated_with::dendritic cells. Platelet derived growth factor is a major inducer of CCL2 gene. To become activated CCL2 protein has to be cleaved by is_associated_with::metalloproteinase MMP-12.

is_associated_with::CCR2 and is_associated_with::CCR4 are two cell surface receptors that bind CCL2.

CCL2 exhibits a chemotactic activity for monocytes and basophils. However, it does not attract neutrophils or eosinophils. After deletion of the N-terminal residue, CCL2 loses its attractivity for basophils and becomes a chemoattractant of eosinophils. Basophils and mast cells that are treated with CCL2 release their granules to the intercellular space. This effect can be also potentiated by a pre-treatment with IL-3 or even by other cytokines. CCL2 augments monocyte anti-tumor activity and it is essential for formation of granulomas.

CCL2 can be found at the sites of tooth eruption and bone degradation. In the bone, CCL2 is expressed by mature is_associated_with::osteoclasts and is_associated_with::osteoblasts and it is under control of nuclear factor κB (NFκB). In the human osteoclasts, CCL2 and is_associated_with::RANTES (regulated on activation normal T cell expressed and secreted). Both MCP-1 and RANTES induce formation of TRAP-positive, multinuclear cells from M-CSF-treated monocytes in the absence of RANKL, but produced osteoclasts that lacked cathepsin K expression and resorptive capacity. It is proposed that CCL2 and RANTES act as is_associated_with::autocrine loop in human osteoclast differentiation.

The CCL2 chemokine is also expressed by neurons, astrocytes and microglia. The expression of CCL2 in neurons is mainly found in the cerebral cortex, globus pallidus, hippocampus, paraventricular and supraoptic hypothalamic nuclei, lateral hypothalamus, substantia nigra, facial nuclei, motor and spinal trigeminal nuclei, gigantocellular reticular nucleus and in Purkinje cells in the cerebellum.

Clinical importance
CCL2 is implicated in pathogeneses of several diseases characterized by monocytic infiltrates, such as is_associated_with::psoriasis, is_associated_with::rheumatoid arthritis and is_associated_with::atherosclerosis.

Administration of anti-CCL2 antibodies in a model of is_associated_with::glomerulonephritis reduces infiltration of macrophages and T cells, reduces crescent formation, as well as scarring and renal impairment.

CCL2 is involved in the neuroinflammatory processes that takes place in the various diseases of the central nervous system (CNS), which are characterized by neuronal degeneration. CCL2 expression in glial cells is increased in epilepsy, brain ischemia Alzheimer’s disease is_associated_with::experimental autoimmune encephalomyelitis (EAE), and traumatic brain injury.

Hypomethylation of CpG sites within the CCL2 promoter region is affected by high levels of blood glucose and TG, which increase CCL2 levels in the blood serum. The later plays an important role in the vascular complications of type 2 diabetes

CCL2 induces is_associated_with::amylin expression through ERK1/ERK2/JNK-AP1 and is_associated_with::NF-κB related signaling pathways independent of is_associated_with::CCR2. Amylin upregulation by CCL2 contributes to the elevation of the plasma amylin and insulin resistance in obesity.

is_associated_with::Adipocytes secrete various is_associated_with::adipokines that may be involved in the negative cross-talk between adipose tissue and skeletal muscle. CCL2 impairs insulin signaling in skeletal muscle cells via ERK1/2 activation at doses similar to its physiological plasma concentrations (200 pg/mL), but does not involve activation of the NF-κB pathway. CCL2 significantly reduced insulin-stimulated glucose uptake in is_associated_with::myocytes. CCL2 may represent a molecular link in the negative cross-talk between adipose tissue and skeletal muscle assigning a completely novel important role to CCL2 besides inflammation.

Incubation of HL-1 is_associated_with::cardiomyocytes and human myocytes with oxidized-LDL induced the expression of BNP and CCL2 genes, while native LDL (N-LDL) had no effect.

Treatment with melatonin in old mice with age related liver inflammation decreased the mRNA expression of TNF-α, IL-1β, HO (HO-1 and HO-2), iNOS, CCL2, NF-κB1, NF-κB2 and NKAP in old male mice. The protein expression of TNF-α, IL-1β was also decreased and IL-10 increased with melatonin treatment. Exogenous administration of is_associated_with::melatonin was able to reduce inflammation.