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Granulocyte-macrophage colony-stimulating factor

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Not to be confused withgranulocyte colony-stimulating factorormacrophage colony-stimulating factor.
CSF2
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesCSF2,GMCSF, colony stimulating factor 2, CSF
External IDsOMIM:138960;MGI:1339752;HomoloGene:600;GeneCards:CSF2;OMA:CSF2 - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 11: 54.14 – 54.14 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Granulocyte-macrophage colony-stimulating factor
three-dimensional structure ofrecombinanthuman granulocyte-macrophage colony-stimulating factor (rhGM_CSF)
Identifiers
SymbolGM_CSF
PfamPF01109
PfamclanCL0053
InterProIPR000773
PROSITEPDOC00584
SCOP22gmf/SCOPe/SUPFAM
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary
Granulocyte-macrophage colony-stimulating factor
Clinical data
ATC code
Identifiers
  • Human granulocyte macrophage colony stimulating factor
CAS Number
DrugBank
ChemSpider
  • none
Chemical and physical data
FormulaC639H1006N168O196S8
Molar mass14434.54g·mol−1
☒NcheckY(what is this?)(verify)

Granulocyte-macrophage colony-stimulating factor(GM-CSF), also known ascolony-stimulating factor 2 (CSF2),is amonomericglycoproteinsecreted bymacrophages,T cells,mast cells,natural killer cells,endothelial cellsandfibroblaststhat functions as acytokine.Thepharmaceuticalanalogs of naturally occurring GM-CSF are calledsargramostimandmolgramostim.

Unlikegranulocyte colony-stimulating factor,which specifically promotesneutrophilproliferation and maturation, GM-CSF affects more cell types, especially macrophages andeosinophils.[5]

Function[edit]

GM-CSF is amonomericglycoproteinthat functions as acytokine—it is awhite blood cellgrowth factor.[6]GM-CSF stimulatesstem cellsto producegranulocytes(neutrophils,eosinophils,andbasophils) andmonocytes.Monocytes exit the circulation and migrate into tissue, whereupon they mature intomacrophagesanddendritic cells.Thus, it is part of theimmune/inflammatorycascade,by which activation of a small number of macrophages can rapidly lead to an increase in their numbers, a process crucial for fightinginfection.[citation needed]

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 viaSTAT3.The cytokine activates macrophages to inhibit fungal survival. It induces deprivation in intracellular free zinc and increases production ofreactive oxygen speciesthat culminate in fungal zinc starvation and toxicity.[9]Thus, GM-CSF facilitates development of the immune system and promotes defense against infections.[citation needed]

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

Genetics[edit]

The human gene has been localized in close proximity to theinterleukin 3gene within aT helpertype 2-associated cytokine gene cluster at chromosome region 5q31, which is known to be associated with interstitial deletions in the5q- syndromeandacute 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 encodinginterleukins 4,5,and13.[12]

Glycosylation[edit]

Human granulocyte-macrophage colony-stimulating factor is glycosylated in its mature form.[citation needed]

History[edit]

GM-CSF was first cloned in 1985, and soon afterwards three potential drug products were being made usingrecombinant DNAtechnology:molgramostimwas made inEscherichia coliand is not glycosylated,sargramostimwas made in yeast, has a leucine instead of proline at position 23 and is somewhat glycosylated, andregramostimwas 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]Immunexwas working onsargramostim(Leukine),[15]andSandozwas 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 autologousbone marrow transplantationunder the trade name Leukine, and passed through several hands, ending up withGenzyme,[19]which was subsequently acquired bySanofi.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. Thisoncolytic herpes virus,namedTalimogene laherparepvec,has been genetically engineered to express human GM-CSF using the tumor cells machinery.[21]

Clinical significance[edit]

GM-CSF is found in high levels in joints withrheumatoid arthritisand blocking GM-CSF as abiological targetmay reduce the inflammation or damage. Some drugs (e.g.otilimab) are being developed toblockGM-CSF.[22]In critically ill patients GM-CSF has been trialled as a therapy for the immunosuppression of critical illness, and has shown promise restoringmonocyte[23]andneutrophil[24]function, although the impact on patient outcomes is currently unclear and awaits larger studies.

GM-CSF stimulatesmonocytesandmacrophagesto produce pro-inflammatory cytokines, includingCCL17.[25]Elevated GM-CSF has been shown to contribute to inflammation ininflammatory arthritis,osteoarthritis,colitisasthma,obesity,andCOVID-19.[25][26][27]

Clinical trials[edit]

Monoclonal antibodiesagainst GM-CSF are being used as treatment in clinical trials againstrheumatoid arthritis,ankylosing spondylitis,and COVID-19.[25]

See also[edit]

References[edit]

  1. ^abcGRCh38: Ensembl release 89: ENSG00000164400–Ensembl,May 2017
  2. ^abcGRCm38: 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): S342-52.doi:10.1086/513857.PMID10081506.
  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.PMID24264600.S2CID24452892.
  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.PMID2001448.
  8. ^Voehringer D (October 2012)."Basophil modulation by cytokine instruction".European Journal of Immunology.42(10): 2544–50.doi:10.1002/eji.201142318.PMID23042651.S2CID23972211.
  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.PMC3841917.PMID24138881.
  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.PMID24954585.
  11. ^Bowers SR, Mirabella F, Calero-Nieto FJ, Valeaux S, Hadjur S, Baxter EW, et al. (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.PMC2655614.PMID19158269.
  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.PMID9845514.
  14. ^"Molgramostim".AdisInsight.Retrieved3 April2018.
  15. ^Staff (May 2008)."Back to the Future: Original Liquid Leukine® Coming Soon"(PDF).Oncology Business Review.Archived fromthe original(PDF)on 2016-08-25.Retrieved2016-08-29.
  16. ^Hussein AM, Ross M, Vredenburgh J, Meisenberg B, Hars V, Gilbert C, et al. (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.PMID7493686.S2CID25424116.
  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.Retrieved12 November2011.
  20. ^U.S. Food & Drug Administration."IMLYGIC (talimogene laherparepvec)".fda.gov.Retrieved17 December2019.
  21. ^Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. (September 2015)."Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma".Journal of Clinical Oncology.33(25): 2780–8.doi:10.1200/JCO.2014.58.3377.PMID26014293.
  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.PMID23448220.S2CID169334.
  23. ^Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, et al. (October 2009). "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): 640–8.doi:10.1164/rccm.200903-0363OC.PMID19590022.
  24. ^Pinder EM, Rostron AJ, Hellyer TP, Ruchaud-Sparagano MH, Scott J, Macfarlane JG, et al. (October 2018)."Randomised controlled trial of GM-CSF in critically ill patients with impaired neutrophil phagocytosis".Thorax.73(10): 918–925.doi:10.1136/thoraxjnl-2017-211323.PMC6166597.PMID30064991.
  25. ^abcLee KM, Achuthan AA, Hamilton JA (2020)."GM-CSF: A Promising Target in Inflammation and Autoimmunity".ImmunoTargets and Therapy.9:225–240.doi:10.2147/ITT.S262566.PMC7605919.PMID33150139.
  26. ^Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, Liew F, Russell CD, Moore SC, et al. (March 2021)."Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19".Science Immunology.6(57): eabg9873.doi:10.1126/sciimmunol.abg9873.PMC8128298.PMID33692097.
  27. ^Zhao Y, Kilian C, Turner JE, Bosurgi L, Roedl K, Bartsch P, et al. (February 2021)."Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients".Science Immunology.6(56).doi:10.1126/sciimmunol.abf6692.PMC8128299.PMID33622974.

External links[edit]

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