CCL2
Encyclopedia
For the ICAO airport code see Candle Lake Airpark
Candle Lake Airpark
Candle Lake Airpark, , is located west northwest of Candle Lake, Saskatchewan, Canada.-External links:* on COPA's Places to Fly airport directory...

, for the diradical compound see Dichlorocarbene
Dichlorocarbene
Dichlorocarbene is a carbene commonly encountered in organic chemistry. This reactive intermediate with chemical formula CCl2 is easily available by reaction of chloroform and a base such as potassium t-butoxide or sodium hydroxide dissolved in water...

.

Chemokine (C-C motif) ligand 2 (CCL2) also known as monocyte chemotactic protein-1 (MCP-1) or small inducible cytokine A2 is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that in humans is encoded by the CCL2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

. CCL2 is a small cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

 belonging to the CC chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...

 family. CCL2 recruits monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

s, memory T cells
Memory T cells
Memory T cells are a subset of infection- as well as potentially cancer-fighting T cells that have previously encountered and responded to their cognate antigen; thus, the term antigen-experienced T cell is often applied. Such T cells can recognize foreign invaders, such as bacteria or viruses,...

, and dendritic cells to sites of tissue injury, infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

, and inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

.

Genomics

As with many other CC chemokines, CCL2 is located on chromosome 17 (17q11.2-q21.1) in humans.The gene spans 1,927 bases and lies on the Watson (plus) strand. The gene has three exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...

s and two intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...

s. It is produced as a protein precursor
Protein precursor
A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein that can be turned into an active form by posttranslational modification. The name of the precursor for a protein is often prefixed by pro...

 containing signal peptide of 23 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s and a mature peptide of 76 amino acids. The predicted weight is 11.025 kiloDaltons (kDa).

In the mouse the homolog is Sig-je.

Population genetics

The levels of this protein vary considerably between normal people. Multivariable-adjusted heritability of CCL2 concentrations in whites of European descent has been reported to be 0.37 in plasma and 0.44 in serum

Molecular biology

It is a monomeric polypeptide, with a molecular weight of approximately 13kDa. It is tethered on endothelial cells by glycosaminoglycan side chains of proteoglycans. It is primarily secreted by monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

s, macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s and dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...

s. It is a platelet derived growth factor inducible gene. It is cleaved by the metalloproteinase
Metalloproteinase
Metalloproteinases constitute a family of enzymes from the group of proteases, classified by the nature of the most prominent functional group in their active site. These are proteolytic enzymes whose catalytic mechanism involves a metal. Most metalloproteases are zinc-dependent, but some use...

 MMP-12.

The cell surface receptors that bind CCL2 are CCR2 and CCR4.

This cytokine displays chemotactic activity for monocytes and basophils but not for neutrophils or
eosinophils. Deletion of the N-terminal residue converts it from an activator of basophils to an eosinophil chemoattractant. CCL2 causes the degranulation of basophils and mast cells, an effect potentiated by pre-treatment with IL-3 and other cytokines. It augments monocyte anti-tumor activity and is essential for granuloma formation

It is found at the site of tooth eruption and bone degradation. In the bone, CCL2 is expressed by mature osteoclast
Osteoclast
An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...

s and osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...

s and is under the control of nuclear factor κB (NFκB). In human osteoclasts, it has been shown that CCL2 and RANTES
RANTES
Chemokine ligand 5 is a protein which in humans is encoded by the CCL5 gene. It is also known as RANTES .- Function :...

 (regulated on activation normal T cell expressed and secreted) are unregulated by RANKL
RANKL
Receptor activator of nuclear factor kappa-B ligand , also known as tumor necrosis factor ligand superfamily member 11 , TNF-related activation-induced cytokine , osteoprotegerin ligand , and osteoclast differentiation factor , is a protein that in humans is encoded by the TNFSF11 gene.RANKL is...

 (receptor activator of NFκB ligand). Both MCP-1 and RANTES were also shown to induce the formation of TRAP-positive
Tartrate resistant acid phosphatase
Tartrate-resistant acid phosphatase or acid phosphatase 5, tartrate resistant is a glycosylated monomeric metalloenzyme expressed in mammals. It has a molecular weight of approximately 35kDa, a basic isoelectric point , and optimal activity in acidic conditions. TRAP is synthesized as latent...

, multinuclear cells from M-CSF-treated monocytes in the absence of RANKL, but produced osteoclasts that lacked cathepsin K
Cathepsin
Cathepsins are proteases: proteins that break apart other proteins, found in many types of cells including those in all animals. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave...

 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 in nervous tissue. Neuronal expression of CCL2 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 has been implicated in the pathogenesis of diseases characterized by monocytic
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

 infiltrates, like psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...

, rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

 and atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

.

Administration of anti-CCL2 antibodies in a model of glomerulonephritis
Glomerulonephritis
Glomerulonephritis, also known as glomerular nephritis, abbreviated GN, is a renal disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys...

 have shown reduced macrophage and T cell infiltration, as well as reduced crescent formation, scarring and renal impairment.

CCL2 is involved in the neuroinflammatory processes that takes place in various central nervous system (CNS) diseases characterized by neuronal degeneration. Its expression by glial cells is increased in epilepsy, brain ischemia Alzheimer’s disease experimental autoimmune encephalomyelitis
Experimental autoimmune encephalomyelitis
Experimental autoimmune encephalomyelitis, sometimes Experimental Allergic Encephalomyelitis is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system...

 (EAE), and traumatic brain injury.

Hypomethylation of CpG sites in the CCL2 promoter region may be affected by blood glucose and TG, which then increase the serum CCL2 level and may play a role in the vascular complications of type 2 diabetes

CCL2 induces amylin
Amylin
Amylin, or Islet Amyloid Polypeptide , is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin .-Clinical significance:...

 expression through ERK1
MAPK3
Mitogen-activated protein kinase 3 is an enzyme that in humans is encoded by the MAPK3 gene.-Interactions:MAPK3 has been shown to interact with PTPN7, SPIB, GTF2I, DUSP3, HDAC4, RPS6KA2, MAP2K1, DUSP6 and MAP2K2.-Further reading:...

/ERK2
MAPK1
Mitogen-activated protein kinase 1, also known as MAPK1, p42MAPK, and ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.- Function :The protein encoded by this gene is a member of the MAP kinase family...

/JNK
C-Jun N-terminal kinases
c-Jun N-terminal kinases , were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet...

-AP1
AP-1 (transcription factor)
In the field of molecular biology, the activator protein 1 is a transcription factor which is a heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families. It regulates gene expression in response to a variety of stimuli, including cytokines, growth factors,...

 and NF-κB related signaling pathways independent of CCR2
CCR2
CCR2, short for chemokine receptor 2, is a chemokine receptor.CCR2 has also recently been designated CD192 .-External links:* at...

. Amylin upregulation by CCL2 may contribute to elevation of plasma amylin in obesity and insulin resistance.

Adipocyte
Adipocyte
However, in some reports and textbooks, the number of fat cell increased in childhood and adolescence. The total number is constant in both obese and lean adult...

s secrete various adipokine
Adipokine
The adipokines or adipocytokines are cytokines secreted by adipose tissue.Members include:* chemerin* interleukin-6...

s 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 myocyte
Myocyte
A myocyte is the type of cell found in muscles. They arise from myoblasts.Each myocyte contains myofibrils, which are long, long chains of sarcomeres, the contractile units of the cell....

s. 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
Brain natriuretic peptide
Brain natriuretic peptide , now known as B-type natriuretic peptide or GC-B, is a 32 amino acid polypeptide secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells...

 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
IL1B
Interleukin-1 beta also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene. IL-1β precursor is cleaved by caspase 1 . Cytosolic thiol protease cleaves the product to form mature IL-1β.- Function :Interleukin 1 was discovered by Gery in 1972...

, HO (HO-1
HMOX1
HMOX1 is a human gene that encodes for the enzyme heme oxygenase 1 . Heme oxygenase is an essential enzyme in heme catabolism, it cleaves heme to form biliverdin....

 and HO-2
HMOX2
Heme oxygenase 2 is an enzyme that in humans is encoded by the HMOX2 gene.- Function :Heme oxygenase, an essential enzyme in heme catabolism, cleaves heme to form biliverdin, which is subsequently converted to bilirubin by biliverdin reductase, and carbon monoxide, a putative neurotransmitter...

), iNOS
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...

, CCL2, NF-κB1
NFKB1
Nuclear factor NF-kappa-B p105 subunit is a protein that in humans is encoded by the NFKB1 gene.This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD protein is a Rel protein-specific transcription inhibitor and...

, NF-κB2
NFKB2
Nuclear factor NF-kappa-B p100 subunit is a protein that in humans is encoded by the NFKB2 gene.-Interactions:NFKB2 has been shown to interact with NFKBIE, BCL3, MAP3K8, BTRC, RELA, RELB, NFKB1, REL and TSC22D3.-Further reading:...

 and NKAP in old male mice. The protein expression of TNF-α, IL-1β
IL1B
Interleukin-1 beta also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene. IL-1β precursor is cleaved by caspase 1 . Cytosolic thiol protease cleaves the product to form mature IL-1β.- Function :Interleukin 1 was discovered by Gery in 1972...

 was also decreased and IL-10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....

 increased with melatonin treatment. Exogenous administration of melatonin
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...

was able to reduce inflammation.

Further reading

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
x
OK