CCL4
   HOME

TheInfoList



OR:

Chemokine (C-C motif) ligands 4 (also CCL4) previously known as
macrophage inflammatory protein Macrophage Inflammatory Proteins (MIP) belong to the family of chemotactic cytokines known as chemokines. In humans, there are two major forms, MIP-1α and MIP-1β that are now (according to the new nomenclature) officially named CCL3 and CCL4, ...
(MIP-1β), is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
which in humans is encoded by the ''CCL4''
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 ...
. ''CCL4'' belongs to a cluster of genes located on 17q11-q21 of the chromosomal region. Identification and localization of the gene on the
chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...
was in 1990 although the discovery of MIP-1 was initiated in 1988 with the purification of a protein doublet corresponding to inflammatory activity from supernatant of endotoxinstimulated murine macrophages. At that time, it was also named as "macrophage inflammatory protein-1" (MIP-1) due to its inflammatory properties. CCL4 is a small
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
that belongs to the CC
chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...
subfamily. CCL4 is being secreted under mitogenic signals and antigens and hereby acts as a chemoattractant for
natural killer cell 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 repres ...
s, monocytes and various other immune cells in the site of inflamed or damaged tissue.


Genomics

In the human genome, CCL4 and many other CC chemokines is encoded by a single gene on
chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...
(17q11-q21). The CCL4 gene consists of three
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s and two
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
s which are separated by 14 kb and are organized in a head to head fashion. MIP-1 genes have 3 untranslated gene regions containing a polyadenylation site (AATAAA) and several AT-rich sequences. The CCL4
protein precursor A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein (or peptide) that can be turned into an active form by post-translational modification, such as breaking off a piece of the molecule or adding on another molecule ...
consist of 92
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s. In turn, the mature CCL4 protein is 92 amino acids long. The CCL4 predicted Mr weight is 7814.8 Da with no apparent N-linked glycosylation site as in other of the MIP-1 proteins.


Molecular structure

CCL4 is a polypeptide chain with a
molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
of approximately 8-10 kDa arranged in a three-dimensional structure in the form of as symmetrical homodimer. Monomeric subunits in their secondary structure composed by a triple-stranded antiparallel sheet form in a Greek key structure on top of which lies an α-helix. NH2-terminus is arranged as a long loop followed by a four-residue helical turn. The overall form of homodimer is globular elongated and cylindrical with sizes: 56 Å × 30 Å × 26 Å in contrast of monomer structure which is similar to IL-8. CCL4 as well as other MIP-1s whether human or mouse have a high tendency to self-aggregation. Aggregation as a reversible and dynamic process depends largely on the concentration of chemokine. The distinction between the CC chemokine families, MIP-1α and MIP-1β, was initially based on whether the first two cysteine residues are separated by one residue (α) or are adjacent (β). Final form of tertiary structure structure of MIP-1 has been defined by heteronuclear magnetic resonance (NMR) analysis. Concentration of this chemokine has been shown to be inversely related with MicroRNA-125b. Concentration of CCL4 within the body increases with age, which may cause chronic inflammation and liver damage.


Function

CCL4 as a chemokine which is produced during inflammation, damage or other important dynamic processes as an angiogenesis to attract immune cells as leukocytes transgress the vascular endothelium and migrate into peripheral tissues. Production of CCL4 CCL4 is produced by:
monocyte 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 inf ...
s,
B cell 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 ...
s,
T cell 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 r ...
s,
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 ...
,
dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
s,
neutrophil 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 ...
s,
fibroblast A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...
s,
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 ...
such as vascular smooth muscle cells, brain microvessel endothelial cells, fetal
microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
and epithelial cells. * Monocytes produce high amounts of CCL4 when they are stimulated with LPS or IL-7 and production is supreesed by IL-4. * T cells and B cells secrete CCL4 response to Ag receptor (BCR) triggering. * NK cells produce CCL4 in response to stimulation with IL-2, physiological activation signals such as lysis. NK cells can be important source of CC chemokines and may suppress HIV infection by inhibition replication of HIV-1 virus by interfering with the ability to utilize CCR5 as a coreceptor for entry in CD4(+) cells. * Dendritic cells secrete and respond to chemokines after stimulation to LPS, TNFα, or CD40 ligand. In maturing of DC production of chemokines have different impact on chemokine receptor function: CCR1 and CCR5 were down-regulated whereas CCR7 were stimulated increased in maturing DC. Production of chemokines provides DC with the capacity to self-regulate their migratory behavior as well as to recruit other cells. * Neutrophils produce CCL4 in the presence of IFN-gamma and its ihibit by IL-10. * Endothelial cells release CCL4 following stimulation with LPS, TNFα, IFN-, or IL-1. CCL4 is a major HIV-suppressive factor produced by CD8+ T cells.
Perforin Perforin-1 is a protein that in humans is encoded by the ''PRF1'' gene and the ''Prf1'' gene in mice. Function Perforin is a pore forming cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and natural killer cells (NK ce ...
-low memory CD8+ T cells that normally synthesize MIP-1-beta. CCL4 is produced by: neutrophils, monocytes, B cells, T cells, fibroblasts, endothelial cells, and epithelial cells.


Interactions

CCL4 has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
CCL3 Chemokine (C-C motif) ligand 3 (CCL3) also known as macrophage inflammatory protein 1-alpha (MIP-1-alpha) is a protein that in humans is encoded by the ''CCL3'' gene. Function CCL3 is a cytokine belonging to the CC chemokine family that is i ...
. CCL4 binds to G protein-Coupled Receptors
CCR5 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. In humans, the ''CCR5'' gene that encodes the CCR5 p ...
and
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 ...
.


See also

*
Macrophage inflammatory protein Macrophage Inflammatory Proteins (MIP) belong to the family of chemotactic cytokines known as chemokines. In humans, there are two major forms, MIP-1α and MIP-1β that are now (according to the new nomenclature) officially named CCL3 and CCL4, ...


References


Further reading

* * * * * * * * * * * * * * * * * * * *


External links

* {{Chemokine receptor modulators