Granulocyte colony-stimulating factor

Not to be confused with granulocyte macrophage colony-stimulating factor.

Colony stimulating factor 3 (granulocyte)
Ribbon diagram showing three molecules of human G-CSF. From PDB: 1rhg​
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1CD9, 1GNC, 1PGR, 1RHG, 2D9Q
Identifiers
Symbols	CSF3 ; C17orf33; CSF3OS; GCSF
External IDs	OMIM: 138970 MGI: 1339751 HomoloGene: 7677 GeneCards: CSF3 Gene
Gene ontology Molecular function • cytokine activity • granulocyte colony-stimulating factor receptor binding • growth factor activity • enzyme binding Cellular component • extracellular space Biological process • immune response • multicellular organismal development • positive regulation of cell proliferation • positive regulation of phosphatidylinositol 3-kinase signaling • cytokine-mediated signaling pathway • positive regulation of actin filament polymerization • granulocyte differentiation • positive regulation of protein binding • positive regulation of peptidyl-serine phosphorylation • positive regulation of transcription factor import into nucleus • positive regulation of myeloid cell differentiation • positive regulation of transcription from RNA polymerase II promoter • positive regulation of peptidyl-tyrosine phosphorylation • positive regulation of protein kinase B signaling • cellular response to lipopolysaccharide • cellular response to cytokine stimulus • negative regulation of neuron death • positive regulation of actin cytoskeleton reorganization Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1440	12985
Ensembl	ENSG00000108342	ENSMUSG00000038067
UniProt	P09919	P09920
RefSeq (mRNA)	NM_000759	NM_009971
RefSeq (protein)	NP_000750	NP_034101
Location (UCSC)	Chr 17: 40.02 – 40.02 Mb	Chr 11: 98.7 – 98.7 Mb
PubMed search	[1]	[2]

Granulocyte-colony stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. Functionally, it is a cytokine and hormone, a type of colony-stimulating factor, and is produced by a number of different tissues. The pharmaceutical analogs of naturally occurring G-CSF are called filgrastim and lenograstim.

G-CSF also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils.

Discovery

Mouse granulocyte-colony stimulating factor (G-CSF) was first recognised and purified in Walter and Eliza Hall Institute, Australia in 1983, and the human form was cloned by groups from Japan and Germany/United States in 1986.

Biological function

G-CSF is produced by endothelium, macrophages, and a number of other immune cells. The natural human glycoprotein exists in two forms, a 174- and 177-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.

White blood cells

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 granulocytes. G-CSF 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.

hematopoietic system

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.

Neurons

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.

Genetics

The gene for G-CSF is located on chromosome 17, locus q11.2-q12. Nagata et al. found that the GCSF gene has 4 introns, 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.

Therapeutic use

Chemotherapy induced neutropenia

Chemotherapy can cause myelosuppression and unacceptably low levels of white blood cells (neutropenia), making patients susceptible to infections and sepsis. G-CSF stimulates the production of granulocytes, a type of white blood cell. In oncology 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. It is administered to oncology patients via subcutaneous or intravenous routes.

A study in mice has shown that G-CSF may decrease bone mineral density.

Before blood donation

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. For this purpose, G-CSF appears to be safe in pregnancy during implantation as well as during the second and third trimesters. Breastfeeding should be withheld for 3 days after CSF administration to allow for clearance of it from the milk. People who have been administered colony-stimulating factors do not have a higher risk of leukemia than people who have not.

Stem cell transplants

G-CSF may also be given to the receiver in hematopoietic stem cell transplantation, to compensate for conditioning regimens.

Research

G-CSF when given early after exposure to radiation may improve white blood cell counts, and is stockpiled for use in radiation incidents.

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.

Due to its neuroprotective properties, 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.

Side effect

Sweet's syndrome is a known side effect of using this drug.

Pharmaceutical variants

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 cells (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.

See also

• PEGylation

External links

• Granulocyte Colony-Stimulating Factor at the US National Library of Medicine Medical Subject Headings (MeSH)