Granulocyte colony-stimulating factor
Encyclopedia
Granulocyte colony-stimulating factor (G-CSF or GCSF) is a colony-stimulating factor
hormone. G-CSF is also known as colony-stimulating factor 3 (CSF 3).
It is a glycoprotein
, growth factor
and cytokine
produced by a number of different tissues
to stimulate the bone marrow
to produce granulocyte
s and stem cell
s. G-CSF then stimulates the bone marrow to release them into the blood.
G-CSF also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils. G-CSF regulates them using Janus kinase (JAK)/signal transducer and activator of transcription (STAT)
and Ras /mitogen-activated protein kinase
(MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal transduction pathway.
in 1983, and the human form was cloned by groups from Japan
and the Germany
/United States
in 1986.
, macrophage
s, and a number of other immune
cells. The natural human glycoprotein exists in two forms, a 174- and 180-amino-acid
-long protein
of molecular weight 19,600 grams per mole. The more-abundant and more-active 174-amino acid form has been used in the development of pharmaceutical products by recombinant DNA
(rDNA) technology.
The G-CSF-receptor
is present on precursor cells in the bone marrow
, and, in response to stimulation by G-CSF, initiates proliferation and differentiation
into mature granulocyte
s. G-CSF is also a potent inducer of HSCs mobilization from the bone marrow into the bloodstream, although it has been shown that it does not directly affect the hematopoietic progenitors that are mobilized.
Beside the effect on the hematopoietic system, G-CSF can also act on neuronal cells as a neurotrophic factor. Indeed, its receptor is expressed by neurons in the brain and spinal cord. The action of G-CSF in the central nervous system is to induce neurogenesis
, to increase the neuroplasticity
and to counteract apoptosis
. These properties are currently under investigations for the development of treatments of neurological diseases such as cerebral ischemia
.
17, locus q11.2-q12. Nagata et al. found that the GCSF gene has 4 intron
s, and that 2 different polypeptides are synthesized from the same gene by differential splicing of mRNA.
The 2 polypeptides differ by the presence or absence of 3 amino acids. Expression studies indicate that both have authentic GCSF activity.
It is thought that stability of the G-CSF mRNA is regulated by an RNA element called the G-CSF factor stem-loop destabilising element
.
and hematology
, a recombinant form of G-CSF is used with certain cancer patients to accelerate recovery from neutropenia
after chemotherapy
, allowing higher-intensity treatment regimens. Chemotherapy can cause myelosuppression and unacceptably low levels of white blood cell
s, making patients prone to infection
s and sepsis
.
G-CSF is also used to increase the number of hematopoietic stem cells in the blood of the donor before collection by leukapheresis
for use in hematopoietic stem cell transplantation. It may also be given to the receiver, to compensate for conditioning regimens.
Itescu planned in 2004 to use G-CSF to treat heart degeneration by injecting it into the blood-stream, plus SDF (stromal cell-derived factor) directly to the heart.
A Washington University School of Medicine
study in mice has shown that G-CSF may decrease bone mineral density.
Thanks to its neuroprotective proprieties, G-CSF is currently under investigation for cerebral ischemia
in a clinical phase IIb and several clinical pilot studies are published for other neurological disease such as amyotrophic lateral sclerosis
.
Sweet's syndrome is a known side effect of using this drug.
It was first marketed by Amgen
with the brand name Neupogen. Several bio-generic versions are now also available in markets such as Europe and Australia.
The recombinant human G-CSF synthesised in an E. coli expression system is called filgrastim
. The structure of filgrastim differs slightly from the structure of the natural glycoprotein. Most published studies have used filgrastim. Filgrastim (Neupogen) and PEG-filgrastim
(Neulasta) are two commercially-available forms of rhG-CSF (recombinant human G-CSF). The PEG (polyethylene glycol
) form has a much longer half-life
, reducing the necessity of daily injections.
Another form of recombinant human G-CSF called lenograstim
is synthesised in Chinese Hamster Ovary cell
s (CHO cells). As this is a mammalian cell expression system, lenograstim is indistinguishable from the 174-amino acid natural human G-CSF. No clinical or therapeutic consequences of the differences between filgrastim and lenograstim have yet been identified, but there are no formal comparative studies.
Colony-stimulating factor
Colony-stimulating factors are secreted glycoproteins that bind to receptor proteins on the surfaces of hemopoietic stem cells, thereby activating intracellular signaling pathways that can cause the cells to proliferate and differentiate into a specific kind of blood cell Colony-stimulating...
hormone. G-CSF is also known as colony-stimulating factor 3 (CSF 3).
It is a glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
, growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
and 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...
produced by a number of different tissues
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
to stimulate the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
to produce granulocyte
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...
s and stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s. G-CSF then stimulates the bone marrow to release them into the blood.
G-CSF also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils. G-CSF regulates them using Janus kinase (JAK)/signal transducer and activator of transcription (STAT)
JAK-STAT signaling pathway
The JAK-STAT signaling pathway transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell. The JAK-STAT system is a major signaling alternative to the second...
and Ras /mitogen-activated protein kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
(MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal transduction pathway.
Discovery
Mouse granulocyte colony-stimulating factor (G-CSF) was first recognised and purified in Walter and Eliza Hall Institute, AustraliaAustralia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
in 1983, and the human form was cloned by groups from Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
and the Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
/United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
in 1986.
Biological function
G-CSF is produced by endotheliumEndothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, 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 a number of other immune
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
cells. The natural human glycoprotein exists in two forms, a 174- and 180-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...
-long 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...
of molecular weight 19,600 grams per mole. The more-abundant and more-active 174-amino acid form has been used in the development of pharmaceutical products by recombinant DNA
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
(rDNA) technology.
The G-CSF-receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
is present on precursor cells in the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
, and, in response to stimulation by G-CSF, initiates proliferation and differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
into mature granulocyte
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...
s. G-CSF is also a potent inducer of HSCs mobilization from the bone marrow into the bloodstream, although it has been shown that it does not directly affect the hematopoietic progenitors that are mobilized.
Beside the effect on the hematopoietic system, G-CSF can also act on neuronal cells as a neurotrophic factor. Indeed, its receptor is expressed by neurons in the brain and spinal cord. The action of G-CSF in the central nervous system is to induce neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
, to increase the neuroplasticity
Neuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...
and to counteract apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. These properties are currently under investigations for the development of treatments of neurological diseases such as cerebral ischemia
Cerebral ischemia
Brain ischemia, also known as cerebral ischemia, is a condition in which there is insufficient blood flow to the brain to meet metabolic demand. This leads to poor oxygen supply or cerebral hypoxia and thus to the death of brain tissue or cerebral infarction / ischemic stroke...
.
Genetics
The gene for G-CSF is located on chromosomeChromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
17, locus q11.2-q12. Nagata et al. found that the GCSF gene has 4 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, and that 2 different polypeptides are synthesized from the same gene by differential splicing of mRNA.
The 2 polypeptides differ by the presence or absence of 3 amino acids. Expression studies indicate that both have authentic GCSF activity.
It is thought that stability of the G-CSF mRNA is regulated by an RNA element called the G-CSF factor stem-loop destabilising element
G-CSF factor stem-loop destabilising element
The G-CSF factor stem-loop destabilising element is an RNA element secreted by fibroblasts and endothelial cells in response to the inflammatory mediators interleukin-1 and tumour necrosis factor-alpha and by activated macrophages. The synthesis of G-CSF is regulated both transcriptionally and...
.
Therapeutic use
G-CSF stimulates the production of white blood cells (WBC). In oncologyOncology
Oncology is a branch of medicine that deals with cancer...
and hematology
Hematology
Hematology, also spelled haematology , is the branch of biology physiology, internal medicine, pathology, clinical laboratory work, and pediatrics that is concerned with the study of blood, the blood-forming organs, and blood diseases...
, a recombinant form of G-CSF is used with certain cancer patients to accelerate recovery from neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
after chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, allowing higher-intensity treatment regimens. Chemotherapy can cause myelosuppression and unacceptably low levels of white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s, making patients prone to 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...
s and sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
.
G-CSF is also used to increase the number of hematopoietic stem cells in the blood of the donor before collection by leukapheresis
Leukapheresis
Leukapheresis is a laboratory procedure in which white blood cells are separated from a sample of blood. It is a specific type of apheresis, the more general term for separating out one particular constituent of blood and returning the remainder to the circulation.Leukapheresis may be performed to...
for use in hematopoietic stem cell transplantation. It may also be given to the receiver, to compensate for conditioning regimens.
Itescu planned in 2004 to use G-CSF to treat heart degeneration by injecting it into the blood-stream, plus SDF (stromal cell-derived factor) directly to the heart.
A Washington University School of Medicine
Washington University School of Medicine
Washington University School of Medicine , located in St. Louis, Missouri, is one of the graduate schools of Washington University in St. Louis. One of the top medical schools in the United States, it is currently ranked 4th for research according to U.S. News and World Report and has been listed...
study in mice has shown that G-CSF may decrease bone mineral density.
Thanks to its neuroprotective proprieties, G-CSF is currently under investigation for cerebral ischemia
Cerebral ischemia
Brain ischemia, also known as cerebral ischemia, is a condition in which there is insufficient blood flow to the brain to meet metabolic demand. This leads to poor oxygen supply or cerebral hypoxia and thus to the death of brain tissue or cerebral infarction / ischemic stroke...
in a clinical phase IIb and several clinical pilot studies are published for other neurological disease such as amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
.
Sweet's syndrome is a known side effect of using this drug.
It was first marketed by Amgen
Amgen
Amgen Inc. is an international biotechnology company headquartered in Thousand Oaks, California. Located in the Conejo Valley, Amgen is the world's largest independent biotech firm. The company employs approximately 17,000 staff members. Its products include Epogen, Aranesp, Enbrel, Kineret,...
with the brand name Neupogen. Several bio-generic versions are now also available in markets such as Europe and Australia.
The recombinant human G-CSF synthesised in an E. coli expression system is called filgrastim
Filgrastim
Filgrastim is a granulocyte colony-stimulating factor analog used to stimulate the proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. ...
. The structure of filgrastim differs slightly from the structure of the natural glycoprotein. Most published studies have used filgrastim. Filgrastim (Neupogen) and PEG-filgrastim
Pegfilgrastim
Pegfilgrastim is a PEGylated form of the recombinant human granulocyte colony-stimulating factor analog, filgrastim. Like GCSF, the pegylated form serves to stimulate the level of white blood cells ....
(Neulasta) are two commercially-available forms of rhG-CSF (recombinant human G-CSF). The PEG (polyethylene glycol
Polyethylene glycol
Polyethylene glycol is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide or polyoxyethylene , depending on its molecular weight, and under the tradename Carbowax.-Available forms:PEG, PEO, or POE refers to an...
) form has a much longer half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
, reducing the necessity of daily injections.
Another form of recombinant human G-CSF called lenograstim
Lenograstim
Lenograstim is a recombinant granulocyte colony-stimulating factor which functions as a immunostimulator. It is developed by Ligand Pharmaceuticals under the brand name Graslopin....
is synthesised in Chinese Hamster Ovary cell
Chinese Hamster Ovary cell
Chinese hamster ovary cells are a cell line derived from the ovary of the Chinese hamster. They are often used in biological and medical research and commercially in the production of therapeutic proteins. They were introduced in the 1960s and grow as a cultured monolayer...
s (CHO cells). As this is a mammalian cell expression system, lenograstim is indistinguishable from the 174-amino acid natural human G-CSF. No clinical or therapeutic consequences of the differences between filgrastim and lenograstim have yet been identified, but there are no formal comparative studies.
Further reading
External links
- http://www.gdb.org/gdb-bin/genera/genera/hgd/GenomicSegment?!action=query&displayName=gcsfGCSF at The GDB Human Genome DatabaseGDB Human Genome DatabaseThe GDB Human Genome Database was a community curated collection of human genomic data. What set GDB apart from other biological databases was its use of world-class leaders in human genetics to act as curators for the data. In order to ensure a high degree of quality, records within GDB were...
]