For the ICAO airport code see Candle Lake Airpark, for the diradical compound
see Dichlorocarbene. The chemokine ligand 2 is also referred
to as monocyte chemotactic protein 1 and small inducible cytokine A2. CCL2 is a
small cytokine that belongs to the CC chemokine family. CCL2 recruits
monocytes, memory T cells, and dendritic cells to the sites of inflammation
produced by either tissue injury or infection.
Genomics In the human genome, CCL2 and many other
CC chemokines are located on chromosome 17. The gene span is 1,927 bases and the
CCL2 gene resides on the Watson strand. The CCL2 gene has three exons and two
introns. The CCL2 protein precursor contains a signal peptide of 23 amino
acids. In turn, the mature CCL2 is 76 amino acids long. The CCL2 predicted
weight is 11.025 kiloDaltons. 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 polypeptide, with a 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 monocytes, macrophages and dendritic cells. Platelet derived growth
factor is a major inducer of CCL2 gene. To become activated CCL2 protein has to
be cleaved by metalloproteinase MMP-12. CCR2 and 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 osteoclasts and osteoblasts and it is
under control of nuclear factor κB. In the human osteoclasts, CCL2 and RANTES.
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 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
psoriasis, rheumatoid arthritis and atherosclerosis.
Administration of anti-CCL2 antibodies in a model of 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, which are characterized by neuronal degeneration.
CCL2 expression in glial cells is increased in epilepsy, brain ischemia
Alzheimer’s disease experimental autoimmune encephalomyelitis, 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 amylin expression through ERK1JNK-AP1 and NF-κB related signaling
pathways independent of CCR2. Amylin upregulation by CCL2 contributes to the
elevation of the plasma amylin and insulin resistance in obesity.
Adipocytes secrete various 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, but does not involve activation of the
NF-κB pathway. CCL2 significantly reduced insulin-stimulated glucose
uptake in 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 cardiomyocytes and human myocytes with oxidized-LDL induced
the expression of BNP and CCL2 genes, while native 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, 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 melatonin was able to reduce inflammation.
References Further reading