Chemokine (C-C motif) ligand 1 (CCL1) is also known as small inducible cytokine A1 and I-309 in humans. CCL1 is a small
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
that belongs to the
CC chemokine
CC, cc, or C-C may refer to:
Arts, entertainment, and media Fictional characters
* C.C. (''Code Geass''), a character in the ''Code Geass'' anime series, pronounced "C-two"
* C.C. Babcock, a character in the American sitcom ''The Nanny''
* Come ...
family.
Genomics
CCL1 is encoded by CCL1
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
which is one of the several chemokine genes clustered on the
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
17q11.2-q12 in humans.
It is expressed by specifically activated
T cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
upon secondary stimulation.
The homologous mouse gene is termed Tca-3.
Discovery
CCL is the first human CCL chemokine that was identified by molecular cloning during searching for genes expressed by
T cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
.
Function
CCL1 is a small
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
with a molecular weight of approximately 15-16 kDa.
CCL1 is secreted by activated
monocytes
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
/
macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
,
T lymphocytes
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
and
endothelial cells
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
.
CCL1 binds to the chemokine
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
CCR8
Chemokine (C-C motif) receptor 8, also known as CCR8, is a protein which in humans is encoded by the ''CCR8'' gene. CCR8 has also recently been designated CDw198 (cluster of differentiation w198).
Function
This gene encodes a member of the bet ...
and induces Ca2+ influx,
chemotaxis
Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
and regulate
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
CCR8
Chemokine (C-C motif) receptor 8, also known as CCR8, is a protein which in humans is encoded by the ''CCR8'' gene. CCR8 has also recently been designated CDw198 (cluster of differentiation w198).
Function
This gene encodes a member of the bet ...
is constitutively expressed in
monocytes
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
/
macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
,
Th2, and
regulatory T lymphocytes.
Thus, CCL1 mainly acts as a
chemoattractant
Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemical ...
for
monocytes
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
/
macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
,
T lymphocyte
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
s, specially
Th2-differentiated T cells and a subset of
T regulatory cells
T, or t, is the twentieth letter in the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''tee'' (pronounced ), plural ''tees''. It is der ...
''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' into inflammatory siter. It can also attract
NK cells
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
, immature
B cells
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
but do not attracts
neutrophils
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
.
CCL1 stimulates a transient increase in the concentration of cytoplasmic free
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
in
monocytes
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
but not in other type of cells.
Furthermore, CCL1 inhibits
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
in thymic cell lines by the RAS/MAPK pathway but can prevent dexamethasone-induced
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
in cultured murine thymic lymphoma cells.
Clinical importance
CCL1 is involved in inflammatory processes through
leukocyte
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
recruitment and could play a crucial role in
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
and other viral and tumoral processes.
For example, CCL1 transcription was increased in primary human
CD4+ T cells expressing T cell
immunoglobulin
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
and protein 3 containing the mucin domain (TIM-3) and was identified as a differentially transcribed
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
in CD4
+ cells T cells expressing TIM-3 that play a role in the regulation anti-tumor immunity.
CCL1 is also overexpressed in ATL cells and mediates an autocrine antiapoptotic loop along CCR8 for
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
growth and survival of leukemic cells.
Due to these facts, the dysregulation of CCL1 can leads in pathogenesis of several diseases. Some single nucleotide polymorphisms (SNPs) in the CCL1
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
are associated with exacerbations of chronic obstructive pulmonary disease (
COPD
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce mu ...
).
CCL1 plays a role in various CNS functions and could be associated with some neuroinflammatory disorders. In addition to other chemokines, such as CCL2, CCL3, and CCL4, the presence of CCL1 has been reported in the development of brain abscesses, most likely leading to an influx of
lymphocytes
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...
and
monocytes
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
and thus to an adaptive immune response.
Because CCL1 binds to the CCR8 receptor, some diseases can be caused by dysregulation and dysfunction of this receptor. For example, CCL1 and CCR8 mRNA expression has been detected in the CNS of mice with experimental autoimmune encephalomyelitis (EAE). However, the CCR8 receptor has also been shown to be associated with phagocytic macrophages and activated microglia in MS lesions and directly correlate with demyelinating activity.
The
CCR8
Chemokine (C-C motif) receptor 8, also known as CCR8, is a protein which in humans is encoded by the ''CCR8'' gene. CCR8 has also recently been designated CDw198 (cluster of differentiation w198).
Function
This gene encodes a member of the bet ...
receptor can serve as a basic receptor for various strains of
HIV-1
The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey, ...
tropical, dual-tropical and macrophage tropics of HIV-1. Thus, CCl1 has also been studied as a possible potent inhibitor of fusion of cells and cells mediated by HIV-1 envelope and viral infection.
Due to the pathologies that can be caused by dysregulation of the CCR8 receptor, some research are focused on the possibilities of inhibiting this receptor. To suppress the apoptotic activity of CCL1, removing three amino acids from the C-terminus of CCL1 reduces CCR8 binding but converts CCL1 to a more potent CCR8 agonist, leading to increased intracellular calcium release and increased antiapoptotic activity.
References
{{Chemokine receptor modulators
Cytokines