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'''Granulocyte-macrophage colony-stimulating factor''' ('''GM-CSF'''), also known as '''colony-stimulating factor 2 (CSF2)''', is a [[monomeric]] [[glycoprotein]] secreted by [[macrophage]]s, [[T cell]]s, [[mast cells]], [[natural killer cell]]s, [[endothelial cell]]s and [[fibroblast]]s that functions as a [[cytokine]]. The [[pharmaceutical drug|pharmaceutical]] analogs of naturally occurring GM-CSF are called [[sargramostim]] and [[molgramostim]].
'''Granulocyte-macrophage colony-stimulating factor''' ('''GM-CSF'''), also known as '''colony-stimulating factor 2 (CSF2)''', is a [[monomeric]] [[glycoprotein]] secreted by [[macrophage]]s, [[T cell]]s, [[mast cells]], [[natural killer cell]]s, [[endothelial cell]]s and [[fibroblast]]s that functions as a [[cytokine]]. The [[pharmaceutical drug|pharmaceutical]] analogs of naturally occurring GM-CSF are called [[sargramostim]] and [[molgramostim]].


Unlike [[granulocyte colony-stimulating factor]], which specifically promotes [[neutrophil]] proliferation and maturation, GM-CSF affects more cell types, especially macrophages and [[eosinophil]]s.<ref name="pmid10081506">{{cite journal | vauthors=Root RK, Dale DC | title=Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: comparisons and potential for use in the treatment of infections in nonneutropenic patients| journal= [[The Journal of Infectious Diseases]] | volume=179 | issue=Suppl 2 | pages=S342-352 | year=1999 | PMID = 10081506 }}</ref>  
Unlike [[granulocyte colony-stimulating factor]], which specifically promotes [[neutrophil]] proliferation and maturation, GM-CSF affects more cell types, especially macrophages and [[eosinophil]]s.<ref name="pmid10081506">{{cite journal | vauthors = Root RK, Dale DC | title = Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: comparisons and potential for use in the treatment of infections in nonneutropenic patients | journal = The Journal of Infectious Diseases | volume = 179 Suppl 2 | issue = Suppl 2 | pages = S342–52 | date = March 1999 | pmid = 10081506 | doi = 10.1086/513857 }}</ref>


== Function ==
== Function ==


GM-CSF is a [[monomeric]] [[glycoprotein]] that functions as a [[cytokine]] — it is a [[white blood cell]] [[growth factor]].<ref name="pmid24264600">{{cite journal | vauthors = Francisco-Cruz A, Aguilar-Santelises M, Ramos-Espinosa O, Mata-Espinosa D, Marquina-Castillo B, Barrios-Payan J, Hernandez-Pando R | title = Granulocyte-macrophage colony-stimulating factor: not just another haematopoietic growth factor | journal = Medical Oncology | volume = 31 | issue = 1 | pages = 774 | date = Jan 2014 | pmid = 24264600 | doi = 10.1007/s12032-013-0774-6 }}</ref> GM-CSF stimulates [[stem cell]]s to produce [[granulocyte]]s ([[neutrophil]]s, [[eosinophil]]s, and [[basophil]]s) and [[monocyte]]s. Monocytes exit the circulation and migrate into tissue, whereupon they mature into [[macrophage]]s and [[dendritic cell]]s. Thus, it is part of the [[immune system|immune]]/[[inflammation|inflammatory]] [[biochemical cascade|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 is a [[monomeric]] [[glycoprotein]] that functions as a [[cytokine]] — it is a [[white blood cell]] [[growth factor]].<ref name="pmid24264600">{{cite journal | vauthors = Francisco-Cruz A, Aguilar-Santelises M, Ramos-Espinosa O, Mata-Espinosa D, Marquina-Castillo B, Barrios-Payan J, Hernandez-Pando R | title = Granulocyte-macrophage colony-stimulating factor: not just another haematopoietic growth factor | journal = Medical Oncology | volume = 31 | issue = 1 | pages = 774 | date = January 2014 | pmid = 24264600 | doi = 10.1007/s12032-013-0774-6 }}</ref> GM-CSF stimulates [[stem cell]]s to produce [[granulocyte]]s ([[neutrophil]]s, [[eosinophil]]s, and [[basophil]]s) and [[monocyte]]s. Monocytes exit the circulation and migrate into tissue, whereupon they mature into [[macrophage]]s and [[dendritic cell]]s. Thus, it is part of the [[immune system|immune]]/[[inflammation|inflammatory]] [[biochemical cascade|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, inhibiting neutrophil migration and causing an alteration of the receptors expressed on the cells surface.<ref>{{cite journal | vauthors = Gasson JC | title = Molecular physiology of granulocyte-macrophage colony-stimulating factor | journal = Blood | volume = 77 | issue = 6 | pages = 1131–45 | date = Mar 1991 | pmid = 2001448 | url = http://www.bloodjournal.org/content/77/6/1131 }}</ref>
GM-CSF also has some effects on mature cells of the immune system. These include, for example, inhibiting neutrophil migration and causing an alteration of the receptors expressed on the cells surface.<ref>{{cite journal | vauthors = Gasson JC | title = Molecular physiology of granulocyte-macrophage colony-stimulating factor | journal = Blood | volume = 77 | issue = 6 | pages = 1131–45 | date = March 1991 | pmid = 2001448 | url = http://www.bloodjournal.org/content/77/6/1131 }}</ref>


GM-CSF signals via signal transducer and activator of transcription, [[STAT5]].<ref name="pmid23042651">{{cite journal | vauthors = Voehringer D | title = Basophil modulation by cytokine instruction | journal = European Journal of Immunology | volume = 42 | issue = 10 | pages = 2544–50 | date = Oct 2012 | pmid = 23042651 | doi = 10.1002/eji.201142318 }}</ref> 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.<ref name="pmid24138881">{{cite journal | vauthors = Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS | title = Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival | journal = Immunity | volume = 39 | issue = 4 | pages = 697–710 | date = Oct 2013 | pmid = 24138881 | pmc = 3841917 | doi = 10.1016/j.immuni.2013.09.006 }}</ref> Thus, GM-CSF facilitates development of the immune system and promotes defense against infections.
GM-CSF signals via signal transducer and activator of transcription, [[STAT5]].<ref name="pmid23042651">{{cite journal | vauthors = Voehringer D | title = Basophil modulation by cytokine instruction | journal = European Journal of Immunology | volume = 42 | issue = 10 | pages = 2544–50 | date = October 2012 | pmid = 23042651 | doi = 10.1002/eji.201142318 }}</ref> 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.<ref name="pmid24138881">{{cite journal | vauthors = Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS | title = Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival | journal = Immunity | volume = 39 | issue = 4 | pages = 697–710 | date = October 2013 | pmid = 24138881 | pmc = 3841917 | doi = 10.1016/j.immuni.2013.09.006 }}</ref> 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.<ref name="pmid24954585">{{cite journal | vauthors = Hansen PJ, Dobbs KB, Denicol AC | title = Programming of the preimplantation embryo by the embryokine colony stimulating factor 2 | journal = Animal Reproduction Science | volume = 149 | issue = 1-2 | pages = 59–66 | date = Sep 2014 | pmid = 24954585 | doi = 10.1016/j.anireprosci.2014.05.017 }}</ref>
GM-CSF also plays a role in embryonic development by functioning as an [[embryokine]] produced by reproductive tract.<ref name="pmid24954585">{{cite journal | vauthors = Hansen PJ, Dobbs KB, Denicol AC | title = Programming of the preimplantation embryo by the embryokine colony stimulating factor 2 | journal = Animal Reproduction Science | volume = 149 | issue = 1–2 | pages = 59–66 | date = September 2014 | pmid = 24954585 | doi = 10.1016/j.anireprosci.2014.05.017 }}</ref>


== Genetics ==
== Genetics ==


The human gene has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the [[5q- syndrome]] and [[acute myelogenous leukemia]]. Genes in the cluster include those encoding [[Interleukin 4|interleukins 4]], [[Interleukin 5|5]], and [[Interleukin 13|13]].<ref>{{cite web| title = Entrez Gene: CSF2 colony stimulating factor 2 (granulocyte-macrophage)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1437| accessdate = }}</ref>
The human gene has been localized in close proximity to the [[interleukin 3]] gene within a [[T helper cell|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.<ref name="pmid19158269">{{cite journal | vauthors = Bowers SR, Mirabella F, Calero-Nieto FJ, Valeaux S, Hadjur S, Baxter EW, Merkenschlager M, Cockerill PN | title = 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 | journal = Molecular and Cellular Biology | volume = 29 | issue = 7 | pages = 1682–93 | date = April 2009 | pmid = 19158269 | pmc = 2655614 | doi = 10.1128/MCB.01411-08 }}</ref> Other genes in the cluster include those encoding [[Interleukin 4|interleukins 4]], [[Interleukin 5|5]], and [[Interleukin 13|13]].<ref>{{cite web | title = Entrez Gene: CSF2 colony stimulating factor 2 (granulocyte-macrophage) | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1437 }}</ref>


== Glycosylation ==
== Glycosylation ==
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== Medical use ==
== Medical use ==


GM-CSF is manufactured using [[recombinant DNA]] technology and is marketed as a [[Biologic medical product|protein therapeutic]] called [[molgramostim]] or, when the protein is expressed in [[yeast]] cells, [[sargramostim]]. It is used as a medication to stimulate the production of white blood cells and thus prevent [[neutropenia]] following [[chemotherapy]].<ref name="pmid24073369">{{cite journal | vauthors = Vacchelli E, Eggermont A, Fridman WH, Galon J, Zitvogel L, Kroemer G, Galluzzi L | title = Trial Watch: Immunostimulatory cytokines | journal = Oncoimmunology | volume = 2 | issue = 7 | pages = e24850 | date = Jul 2013 | pmid = 24073369 | pmc = 3782010 | doi = 10.4161/onci.24850 }}</ref>
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 glyocylated, 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.<ref>{{cite journal | vauthors = Armitage JO | title = Emerging applications of recombinant human granulocyte-macrophage colony-stimulating factor | journal = Blood | volume = 92 | issue = 12 | pages = 4491–508 | date = December 1998 | pmid = 9845514 | url = http://www.bloodjournal.org/content/bloodjournal/92/12/4491.full.pdf?sso-checked=true }}</ref>


GM-CSF has also been evaluated in clinical trials for its potential as a vaccine [[adjuvant]] in HIV-infected patients.<ref name=pmid23111169>{{cite journal | vauthors = Hellerstein M, Xu Y, Marino T, Lu S, Yi H, Wright ER, Robinson HL | title = Co-expression of HIV-1 virus-like particles and granulocyte-macrophage colony stimulating factor by GEO-D03 DNA vaccine | journal = Human Vaccines & Immunotherapeutics | volume = 8 | issue = 11 | pages = 1654–8 | date = Nov 2012 | pmid = 23111169 | doi = 10.4161/hv.21978 | pmc=3601140}}</ref><ref name=pmid26344473 >{{cite journal | vauthors = Iyer SS, Amara RR | title = DNA/MVA Vaccines for HIV/AIDS | journal = Vaccines | volume = 2 | issue = 1 | pages = 160–78 | pmid = 26344473 | doi = 10.3390/vaccines2010160 | pmc=4494194 | year=2014}}</ref>
At that time, [[Genetics Institute, Inc.]] was working on molgramostim,<ref>{{cite web|title=Molgramostim|url=https://adisinsight.springer.com/drugs/800004167|publisher=AdisInsight|access-date=3 April 2018|language=en}}</ref> [[Immunex]] was working on [[sargramostim]] (Leukine),<ref name=back>{{cite journal|last1=Staff|title=Back to the Future: Original Liquid Leukine® Coming Soon|journal=Oncology Business Review|date=May 2008|url=https://obroncology.com/documents/OBR_may08_LEUKINE.pdf}}</ref> and [[Sandoz]] was working on regramostim.<ref>{{cite journal | vauthors = Hussein AM, Ross M, Vredenburgh J, Meisenberg B, Hars V, Gilbert C, Petros WP, Coniglio D, Kurtzberg J, Rubin P | title = 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 | journal = European Journal of Haematology | volume = 55 | issue = 5 | pages = 348–56 | date = November 1995 | pmid = 7493686 }}</ref>


=== Sargramostim ===
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.<ref>{{cite web|title=Press release: Novartis Oncology sharpens focus on key growth drivers|url=https://www.sec.gov/Archives/edgar/data/1114448/000091205702040732/a2092547z6-k.htm|publisher=Novartis via SEC Edgar|date=30 October 2002}}</ref><ref>{{cite web|title=Scientific Conclusions and Grounds for Amendment of the Summary of Product Characteristics Presented by the EMEA|url=http://ec.europa.eu/health/documents/community-register/2000/200006273658/anx_3658_en.pdf|publisher=EMA CPMP|date=27 June 2000}}</ref>
The sequence of human [[GM-CSF]] was first identified in 1985 and soon three recominbant human GM-CSFs were produced, one in bacteria, one in mammalian cells, and one in yeast;<ref name=Blood1998rev>{{cite journal | vauthors = Armitage JO | title = Emerging applications of recombinant human granulocyte-macrophage colony-stimulating factor | journal = Blood | volume = 92 | issue = 12 | pages = 4491–508 | date = December 1998 | pmid = 9845514 | url = http://www.bloodjournal.org/content/92/12/4491?sso-checked=true }}</ref> [[Immunex]] developed GM-CSF manufactured in yeast into [[sargramostim]] ( Leukine).<ref name=back>{{cite journal|last1=Staff|title=Back to the Future: Original Liquid Leukine® Coming Soon|journal=Oncology Business Review|date=May 2008|url=https://obroncology.com/documents/OBR_may08_LEUKINE.pdf}}</ref> Clinical trials of sargramostim were initiated in 1987;<ref name=Immunexhist/> in that same year it was administered to six people as part of a compassionate-use protocol for the victims of cesium irradiation from the [[Goiânia accident]].<ref>{{cite web|author = Schmeck HM | url = https://www.nytimes.com/1987/11/02/world/radiation-team-sent-to-brazil-saves-two-with-a-new-drug.html | title = Radiation Team Sent to Brazil Saves Two With a New Drug | publisher = New York Times | date = 1987-11-02 | accessdate = 2012-06-20 }}</ref>


It was approved by the FDA in March 1991 under the trade name Leukine for acceleration of white blood cell recovery following autologous [[bone marrow transplantation]] in patients with [[non-Hodgkin's lymphoma]], [[acute lymphocytic leukemia]], or [[Hodgkin's disease]].<ref name="urlDetails of Approved Claims by Line of Therapy">{{cite web|url=http://www.accessdata.fda.gov/scripts/cder/onctools/yearlistclaim.cfm?Approv_Date=1991 |title=Approval Summary for sargramostim |accessdate=20 September 2009 |date=1991-03-05 |work=Oncology Tools |publisher=U.S. Food and Drug Administration, Center for Drug Evaluation and Research |archiveurl=https://web.archive.org/web/20070624223312/http://www.accessdata.fda.gov/scripts/cder/onctools/summary.cfm?ID=353 |archivedate=24 June 2007 |deadurl=yes |df= }}</ref> In November 1996, the FDA also approved sargramostim for treatment of [[mycosis|fungal infections]] and replenishment of  white blood cells following chemotherapy.<ref name="urlNewly Approved Drug Therapies (179): Leukine (sargramostim), Immunex">{{cite web| url = http://www.centerwatch.com/patient/drugs/dru179.html | title = Newly Approved Drug Therapies (179): Leukine (sargramostim), Immunex | publisher = CenterWatch  | accessdate = 2008-10-12 }}</ref>  A liquid formulation was approved in 1995.<ref name=back/>  Immunex was acquired by [[Amgen]] in 2002.<ref name=Immunexhist/>  As part of the acquisition,  Leukine was spun off to [[Berlex]], which became [[Bayer HealthCare]] in 2007.<ref name=back/>  In 2009, [[Genzyme]] acquired the rights to Leukine from Bayer, including the manufacturing facility in the Seattle area.<ref name=Immunexhist>{{cite web |url=http://www.fundinguniverse.com/company-histories/Immunex-Corporation-company-History.html |title=Immunex Corporation |author= |work=Company Histories & Profiles |publisher=FundingUniverse.com |accessdate=12 November 2011}}</ref><ref>{{cite web |url=http://www.pharmaceutical-technology.com/projects/berlex/ |title=Bayer Healthcare Pharmaceuticals Plant, Snohomish County, Washington State |author= |work= |publisher=pharmaceutical-technology.com |accessdate=12 November 2011}}</ref><ref>{{cite web |url=http://www.genzyme.com/corp/media/GENZ%20PR-033109.asp |title=Genzyme and Bayer HealthCare Enter New Strategic Agreement |author= |date=March 31, 2009 |work= |publisher=Genzyme |accessdate=12 November 2011 |deadurl=yes |archiveurl=https://web.archive.org/web/20120425073445/http://www.genzyme.com/corp/media/GENZ%20PR-033109.asp |archivedate=25 April 2012 |df= }}</ref>
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]]<ref>{{cite web |url=http://www.pharmaceutical-technology.com/projects/berlex/ |title=Bayer Healthcare Pharmaceuticals Plant, Snohomish County, Washington State |author= |website= |publisher=pharmaceutical-technology.com |access-date=12 November 2011}}</ref> which subsequently was acquired by [[Sanofi]]. Leukine is now owned by Partner Therapeutics (PTx).


=== Rheumatoid arthritis ===
==Research directions==


GM-CSF is found in high levels in joints with [[rheumatoid arthritis]] and blocking GM-CSF may reduce the inflammation or damage. Some drugs (e.g. [[MOR103]]) are being developed to ''block'' GM-CSF.<ref name="pmid23448220">{{cite journal | vauthors = Deiß A, Brecht I, Haarmann A, Buttmann M | title = Treating multiple sclerosis with monoclonal antibodies: a 2013 update | journal = Expert Review of Neurotherapeutics | volume = 13 | issue = 3 | pages = 313–35 | date = Mar 2013 | pmid = 23448220 | doi = 10.1586/ern.13.17 }}</ref>
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. [[MOR103]]) are being developed to ''block'' GM-CSF.<ref name="pmid23448220">{{cite journal | vauthors = Deiß A, Brecht I, Haarmann A, Buttmann M | title = Treating multiple sclerosis with monoclonal antibodies: a 2013 update | journal = Expert Review of Neurotherapeutics | volume = 13 | issue = 3 | pages = 313–35 | date = March 2013 | pmid = 23448220 | doi = 10.1586/ern.13.17 }}</ref> In critically ill patients GM-CSF has been trialled as a therapy for the immunosuppression of critical illness, and has shown promise restoring [[monocyte]]<ref>{{Cite journal|last=Meisel|first=Christian|last2=Schefold|first2=Joerg C.|last3=Pschowski|first3=Rene|last4=Baumann|first4=Tycho|last5=Hetzger|first5=Katrin|last6=Gregor|first6=Jan|last7=Weber-Carstens|first7=Steffen|last8=Hasper|first8=Dietrich|last9=Keh|first9=Didier|date=2009-10-01|title=Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial|journal=American Journal of Respiratory and Critical Care Medicine|volume=180|issue=7|pages=640–648|doi=10.1164/rccm.200903-0363OC|issn=1535-4970|pmid=19590022}}</ref> and [[neutrophil]]<ref>{{Cite journal|last=Pinder|first=Emma M.|last2=Rostron|first2=Anthony J.|last3=Hellyer|first3=Thomas P.|last4=Ruchaud-Sparagano|first4=Marie-Helene|last5=Scott|first5=Jonathan|last6=Macfarlane|first6=James G.|last7=Wiscombe|first7=Sarah|last8=Widdrington|first8=John D.|last9=Roy|first9=Alistair I.|date=2018-07-31|title=Randomised controlled trial of GM-CSF in critically ill patients with impaired neutrophil phagocytosis|journal=Thorax|pages=thoraxjnl-2017-211323|doi=10.1136/thoraxjnl-2017-211323|issn=1468-3296|pmid=30064991}}</ref> function, although the impact on patient outcomes is currently unclear and awaits larger studies.


== See also ==
== See also ==
Line 85: Line 84:


== References ==
== References ==
{{Reflist|500px}}
{{Reflist|32em}}


== External links ==
== External links ==

Latest revision as of 14:17, 14 September 2018

Not to be confused with granulocyte colony-stimulating factor or macrophage colony-stimulating factor.
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Wikidata
View/Edit Human
Granulocyte-macrophage colony-stimulating factor
File:PDB 1csg EBI.jpg
three-dimensional structure of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM_CSF)
Identifiers
SymbolGM_CSF
PfamPF01109
Pfam clanCL0053
InterProIPR000773
PROSITEPDOC00584
SCOP2gmf
SUPERFAMILY2gmf
Granulocyte-macrophage colony-stimulating factor
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  • none
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC639H1006N168O196S8
Molar mass14434.5 g/mol
 ☒N☑Y (what is this?)  (verify)

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.

Unlike granulocyte colony-stimulating factor, which specifically promotes neutrophil proliferation and maturation, GM-CSF affects more cell types, especially macrophages and eosinophils.[1]

Function

GM-CSF is a monomeric glycoprotein that functions as a cytokine — it is a white blood cell growth factor.[2] 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, inhibiting neutrophil migration and causing an alteration of the receptors expressed on the cells surface.[3]

GM-CSF signals via signal transducer and activator of transcription, STAT5.[4] 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.[5] 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.[6]

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.[7] Other genes in the cluster include those encoding interleukins 4, 5, and 13.[8]

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 glyocylated, 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.[9]

At that time, Genetics Institute, Inc. was working on molgramostim,[10] Immunex was working on sargramostim (Leukine),[11] and Sandoz was working on regramostim.[12]

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.[13][14]

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[15] which subsequently was acquired by Sanofi. Leukine is now owned by Partner Therapeutics (PTx).

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. MOR103) are being developed to block GM-CSF.[16] In critically ill patients GM-CSF has been trialled as a therapy for the immunosuppression of critical illness, and has shown promise restoring monocyte[17] and neutrophil[18] function, although the impact on patient outcomes is currently unclear and awaits larger studies.

See also

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ Gasson JC (March 1991). "Molecular physiology of granulocyte-macrophage colony-stimulating factor". Blood. 77 (6): 1131–45. PMID 2001448.
  4. ↑ Voehringer D (October 2012). "Basophil modulation by cytokine instruction". European Journal of Immunology. 42 (10): 2544–50. doi:10.1002/eji.201142318. PMID 23042651.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ "Entrez Gene: CSF2 colony stimulating factor 2 (granulocyte-macrophage)".
  9. ↑ Armitage JO (December 1998). "Emerging applications of recombinant human granulocyte-macrophage colony-stimulating factor" (PDF). Blood. 92 (12): 4491–508. PMID 9845514.
  10. ↑ "Molgramostim". AdisInsight. Retrieved 3 April 2018.
  11. ↑ Staff (May 2008). "Back to the Future: Original Liquid Leukine® Coming Soon" (PDF). Oncology Business Review.
  12. ↑ 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. PMID 7493686.
  13. ↑ "Press release: Novartis Oncology sharpens focus on key growth drivers". Novartis via SEC Edgar. 30 October 2002.
  14. ↑ "Scientific Conclusions and Grounds for Amendment of the Summary of Product Characteristics Presented by the EMEA" (PDF). EMA CPMP. 27 June 2000.
  15. ↑ "Bayer Healthcare Pharmaceuticals Plant, Snohomish County, Washington State". pharmaceutical-technology.com. Retrieved 12 November 2011.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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: thoraxjnl-2017–211323. doi:10.1136/thoraxjnl-2017-211323. ISSN 1468-3296. PMID 30064991.

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