Granulocyte-macrophage colony-stimulating factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that functions as a cytokine. The pharmaceutical analogs of naturally occurring GM-CSF are called sargramostim and molgramostim.

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

CSF2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1CSG, 2GMF, 4NKQ, 5C7X, 5D70, 5D71, 5D72, 4RS1
Identifiers
Aliases	CSF2, GMCSF, colony stimulating factor 2, CSF
External IDs	OMIM: 138960 MGI: 1339752 HomoloGene: 600 GeneCards: CSF2
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q31.1 Start 132,073,789 bp[1] End 132,076,170 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 B1.3|11 32.13 cM Start 54,247,271 bp[2] End 54,249,667 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • growth factor activity • granulocyte macrophage colony-stimulating factor receptor binding • GO:0001948 protein binding • protein tyrosine kinase activity • Ras guanyl-nucleotide exchange factor activity • cytokine activity Cellular component • extracellular region • intracellular membrane-bounded organelle • extracellular Biological process • negative regulation of cytolysis • positive regulation of macrophage derived foam cell differentiation • regulation of cell proliferation • MAPK cascade • positive regulation of podosome assembly • negative regulation of extrinsic apoptotic signaling pathway in absence of ligand • positive regulation of interleukin-23 production • positive regulation of gene expression • embryonic placenta development • epithelial fluid transport • regulation of gene expression • dendritic cell differentiation • myeloid dendritic cell differentiation • macrophage activation • cellular response to lipopolysaccharide • immune response • monocyte differentiation • response to fluid shear stress • response to silicon dioxide • neutrophil differentiation • peptidyl-tyrosine phosphorylation • regulation of circadian sleep/wake cycle, sleep • histamine secretion • positive regulation of tyrosine phosphorylation of STAT protein • cellular response to granulocyte macrophage colony-stimulating factor stimulus • regulation of myeloid cell differentiation • regulation of receptor activity • negative regulation of transcription, DNA-templated • cytokine-mediated signaling pathway • positive regulation of cell proliferation • macrophage differentiation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1437	12981
Ensembl	ENSG00000164400	ENSMUSG00000018916
UniProt	P04141	P01587
RefSeq (mRNA)	NM_000758	NM_009969
RefSeq (protein)	NP_000749	NP_034099
Location (UCSC)	Chr 5: 132.07 – 132.08 Mb	Chr 11: 54.25 – 54.25 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Granulocyte-macrophage colony-stimulating factor
three-dimensional structure of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM_CSF)
Identifiers
Symbol	GM_CSF
Pfam	PF01109
Pfam clan	CL0053
InterPro	IPR000773
PROSITE	PDOC00584
SCOPe	2gmf / SUPFAM
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Granulocyte-macrophage colony-stimulating factor

Clinical data
ATC code	L03AA09 (WHO)
Identifiers
IUPAC name Human granulocyte macrophage colony stimulating factor
CAS Number	83869-56-1^Y
DrugBank	DB00020^N
ChemSpider	none
Chemical and physical data
Formula	C639H1006N168O196S8
Molar mass	14434.54 g·mol^−1
^NY (what is this?)  (verify)

Unlike granulocyte colony-stimulating factor, which specifically promotes neutrophil proliferation and maturation, GM-CSF affects more cell types, especially macrophages and eosinophils.[5]

Function

GM-CSF is a monomeric glycoprotein that functions as a cytokine — it is a white blood cell growth factor.[6] GM-CSF stimulates stem cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes. Monocytes exit the circulation and migrate into tissue, whereupon they mature into macrophages and dendritic cells. Thus, it is part of the immune/inflammatory cascade, by which activation of a small number of macrophages can rapidly lead to an increase in their numbers, a process crucial for fighting infection.

GM-CSF also has some effects on mature cells of the immune system. These include, for example, enhancing neutrophil migration and causing an alteration of the receptors expressed on the cells surface.[7]

GM-CSF signals via signal transducer and activator of transcription, STAT5.[8] In macrophages, it has also been shown to signal via STAT3. The cytokine activates macrophages to inhibit fungal survival. It induces deprivation in intracellular free zinc and increases production of reactive oxygen species that culminate in fungal zinc starvation and toxicity.[9] Thus, GM-CSF facilitates development of the immune system and promotes defense against infections.

GM-CSF also plays a role in embryonic development by functioning as an embryokine produced by reproductive tract.[10]

Genetics

The human gene has been localized in close proximity to the interleukin 3 gene within a T helper type 2-associated cytokine gene cluster at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. GM-CSF and IL-3 are separated by an insulator element and thus independently regulated.[11] Other genes in the cluster include those encoding interleukins 4, 5, and 13.[12]

Glycosylation

Human granulocyte-macrophage colony-stimulating factor is glycosylated in its mature form.

Medical use

GM-CSF was first cloned in 1985, and soon afterwards three potential drug products were being made using recombinant DNA technology: molgramostim was made in Escherichia coli and is not glycosylated, sargramostim was made in yeast, has a leucine instead of proline at position 23 and is somewhat glycosylated, and regramostim was made in Chinese hamster ovary cells (CHO) and has more glycosylation than sargramostim. The amount of glycosylation affects how the body interacts with the drug and how the drug interacts with the body.[13]

At that time, Genetics Institute, Inc. was working on molgramostim,[14] Immunex was working on sargramostim (Leukine),[15] and Sandoz was working on regramostim.[16]

Molgramostim was eventually co-developed and co-marketed by Novartis and Schering-Plough under the trade name Leucomax for use in helping white blood cell levels recover following chemotherapy, and in 2002 Novartis sold its rights to Schering-Plough.[17][18]

Sargramostim was approved by the US FDA in 1991 to accelerate white blood cell recovery following autologous bone marrow transplantation under the trade name Leukine, and passed through several hands, ending up with Genzyme[19] which subsequently was acquired by Sanofi. Leukine is now owned by Partner Therapeutics (PTx).

Imlygic was approved by the US FDA in October 2015,[20] and in December 2015 by the EMA, as an oncolytic virotherapy, commercialized by Amgen Inc. This oncolytic herpes virus, named Talimogene laherparepvec, has been genetically engineered to express human GM-CSF using the tumor cells machinery.[21]

Research directions

GM-CSF is found in high levels in joints with rheumatoid arthritis and blocking GM-CSF as a biological target may reduce the inflammation or damage. Some drugs (e.g. otilimab) are being developed to block GM-CSF.[22] In critically ill patients GM-CSF has been trialled as a therapy for the immunosuppression of critical illness, and has shown promise restoring monocyte[23] and neutrophil[24] function, although the impact on patient outcomes is currently unclear and awaits larger studies.

See also

• CFU-GM
• Granulocyte-macrophage colony-stimulating factor receptor
• Filgrastim (Neupogen, a granulocyte colony-stimulating factor (G-CSF) analog)
• Pegfilgrastim (Neulasta, a PEGylated form filgrastim)

References

1. GRCh38: Ensembl release 89: ENSG00000164400 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000018916 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Root RK, Dale DC (March 1999). "Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: comparisons and potential for use in the treatment of infections in nonneutropenic patients". The Journal of Infectious Diseases. 179 Suppl 2 (Suppl 2): S342–52. doi:10.1086/513857. PMID 10081506.
6. Francisco-Cruz A, Aguilar-Santelises M, Ramos-Espinosa O, Mata-Espinosa D, Marquina-Castillo B, Barrios-Payan J, Hernandez-Pando R (January 2014). "Granulocyte-macrophage colony-stimulating factor: not just another haematopoietic growth factor". Medical Oncology. 31 (1): 774. doi:10.1007/s12032-013-0774-6. PMID 24264600.
7. Gasson JC (March 1991). "Molecular physiology of granulocyte-macrophage colony-stimulating factor". Blood. 77 (6): 1131–45. doi:10.1182/blood.V77.6.1131.1131. PMID 2001448. Archived from the original on 2019-03-14. Retrieved 2015-11-17.
8. Voehringer D (October 2012). "Basophil modulation by cytokine instruction". European Journal of Immunology. 42 (10): 2544–50. doi:10.1002/eji.201142318. PMID 23042651.
9. Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS (October 2013). "Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival". Immunity. 39 (4): 697–710. doi:10.1016/j.immuni.2013.09.006. PMC 3841917. PMID 24138881.
10. Hansen PJ, Dobbs KB, Denicol AC (September 2014). "Programming of the preimplantation embryo by the embryokine colony stimulating factor 2". Animal Reproduction Science. 149 (1–2): 59–66. doi:10.1016/j.anireprosci.2014.05.017. PMID 24954585.
11. Bowers SR, Mirabella F, Calero-Nieto FJ, Valeaux S, Hadjur S, Baxter EW, Merkenschlager M, Cockerill PN (April 2009). "A conserved insulator that recruits CTCF and cohesin exists between the closely related but divergently regulated interleukin-3 and granulocyte-macrophage colony-stimulating factor genes". Molecular and Cellular Biology. 29 (7): 1682–93. doi:10.1128/MCB.01411-08. PMC 2655614. PMID 19158269.
12. "Entrez Gene: CSF2 colony stimulating factor 2 (granulocyte-macrophage)".
13. Armitage JO (December 1998). "Emerging applications of recombinant human granulocyte-macrophage colony-stimulating factor" (PDF). Blood. 92 (12): 4491–508. doi:10.1182/blood.V92.12.4491. PMID 9845514.
14. "Molgramostim". AdisInsight. Retrieved 3 April 2018.
15. Staff (May 2008). "Back to the Future: Original Liquid Leukine® Coming Soon" (PDF). Oncology Business Review. Archived from the original (PDF) on 2016-08-25. Retrieved 2016-08-29.
16. Hussein AM, Ross M, Vredenburgh J, Meisenberg B, Hars V, Gilbert C, Petros WP, Coniglio D, Kurtzberg J, Rubin P (November 1995). "Effects of granulocyte-macrophage colony stimulating factor produced in Chinese hamster ovary cells (regramostim), Escherichia coli (molgramostim) and yeast (sargramostim) on priming peripheral blood progenitor cells for use with autologous bone marrow after high-dose chemotherapy". European Journal of Haematology. 55 (5): 348–56. doi:10.1111/j.1600-0609.1995.tb00713.x. PMID 7493686.
17. "Press release: Novartis Oncology sharpens focus on key growth drivers". Novartis via SEC Edgar. 30 October 2002.
18. "Scientific Conclusions and Grounds for Amendment of the Summary of Product Characteristics Presented by the EMEA" (PDF). EMA CPMP. 27 June 2000.
19. "Bayer Healthcare Pharmaceuticals Plant, Snohomish County, Washington State". pharmaceutical-technology.com. Retrieved 12 November 2011.
20. U.S. Food & Drug Administration. "IMLYGIC (talimogene laherparepvec)". fda.gov. Retrieved 17 December 2019.
21. Andtbacka, Robert H. I.; Kaufman, Howard L.; Collichio, Frances; Amatruda, Thomas; Senzer, Neil; Chesney, Jason; Delman, Keith A.; Spitler, Lynn E.; Puzanov, Igor; Agarwala, Sanjiv S.; Milhem, Mohammed; Cranmer, Lee; Curti, Brendan; Lewis, Karl; Ross, Merrick; Guthrie, Troy; Linette, Gerald P.; Daniels, Gregory A.; Harrington, Kevin; Middleton, Mark R.; Miller, Wilson H.; Zager, Jonathan S.; Ye, Yining; Yao, Bin; Li, Ai; Doleman, Susan; VanderWalde, Ari; Gansert, Jennifer; Coffin, Robert S. (2015-09-01). "Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma". Journal of Clinical Oncology. 33 (25): 2780–2788. doi:10.1200/JCO.2014.58.3377. ISSN 1527-7755. PMID 26014293.
22. Deiß A, Brecht I, Haarmann A, Buttmann M (March 2013). "Treating multiple sclerosis with monoclonal antibodies: a 2013 update". Expert Review of Neurotherapeutics. 13 (3): 313–35. doi:10.1586/ern.13.17. PMID 23448220.
23. Meisel, Christian; Schefold, Joerg C.; Pschowski, Rene; Baumann, Tycho; Hetzger, Katrin; Gregor, Jan; Weber-Carstens, Steffen; Hasper, Dietrich; Keh, Didier (2009-10-01). "Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial". American Journal of Respiratory and Critical Care Medicine. 180 (7): 640–648. doi:10.1164/rccm.200903-0363OC. ISSN 1535-4970. PMID 19590022.
24. Pinder, Emma M.; Rostron, Anthony J.; Hellyer, Thomas P.; Ruchaud-Sparagano, Marie-Helene; Scott, Jonathan; Macfarlane, James G.; Wiscombe, Sarah; Widdrington, John D.; Roy, Alistair I. (2018-07-31). "Randomised controlled trial of GM-CSF in critically ill patients with impaired neutrophil phagocytosis". Thorax. 73 (10): thoraxjnl–2017–211323. doi:10.1136/thoraxjnl-2017-211323. ISSN 1468-3296. PMC 6166597. PMID 30064991.

External links

• Official gentaur web site
• Official Leukine web site
• Granulocyte-Macrophage+Colony-Stimulating+Factor at the US National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P04141 (Granulocyte-macrophage colony-stimulating factor) at the PDBe-KB.