Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Granulocyte-macrophage colony-stimulating factor: Difference between pages

{{Short description|Mammalian protein found in Homo sapiens}}

{{Distinguish|granulocyte colony-stimulating factor|macrophage colony-stimulating factor}}

{{Infobox_gene}}

{{Infobox protein family

| Symbol = GM_CSF

| Name = Granulocyte-macrophage colony-stimulating factor

| image = PDB 1csg EBI.jpg

| width =

| caption = three-dimensional structure of [[recombinant DNA|recombinant]] human granulocyte-macrophage colony-stimulating factor (rhGM_CSF)

| Pfam = PF01109

| Pfam_clan = CL0053

| InterPro = IPR000773

| SMART =

| PROSITE = PDOC00584

| MEROPS =

| SCOP = 2gmf

| TCDB =

| OPM family =

| OPM protein =

| CAZy =

| CDD =

}}

| Verifiedfields = changed

| verifiedrevid = 476997210

<!-- Clinical data -->

| tradename =

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|??}}

| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| DrugBank = DB00020

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = none

<!-- Chemical data -->

| C=639 | H=1006 | N=168 | O=196 | S=8

'''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 = S342-52 | date = March 1999 | pmid = 10081506 | doi = 10.1086/513857 | doi-access = free }}</ref>

== 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 = January 2014 | pmid = 24264600 | doi = 10.1007/s12032-013-0774-6 | s2cid = 24452892 }}</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]].{{cn|date=April 2023}}

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.<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 | doi = 10.1182/blood.V77.6.1131.1131 | doi-access = free }}</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 = October 2012 | pmid = 23042651 | doi = 10.1002/eji.201142318 | s2cid = 23972211 | doi-access = free }}</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.{{cn|date=April 2023}}

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 ==

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 | display-authors = 6 | 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 ==

Human granulocyte-macrophage colony-stimulating factor is glycosylated in its mature form.{{cn|date=April 2023}}

== History ==

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.<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 | doi = 10.1182/blood.V92.12.4491 | url = http://www.bloodjournal.org/content/bloodjournal/92/12/4491.full.pdf?sso-checked=true }}</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|access-date=2016-08-29|archive-url=https://web.archive.org/web/20160825034301/https://obroncology.com/documents/OBR_may08_LEUKINE.pdf|archive-date=2016-08-25|url-status=dead}}</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 | display-authors = 6 | 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 | doi = 10.1111/j.1600-0609.1995.tb00713.x | s2cid = 25424116 }}</ref>

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>

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 |publisher=pharmaceutical-technology.com |access-date=12 November 2011}}</ref> which was subsequently acquired by [[Sanofi]]. Leukine is now owned by Partner Therapeutics (PTx).

Imlygic was approved by the US FDA in October 2015,<ref>{{cite web |url=https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/imlygic-talimogene-laherparepvec |title=IMLYGIC (talimogene laherparepvec) |author= U.S. Food & Drug Administration |publisher=fda.gov |access-date=17 December 2019}}</ref> 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.<ref>{{cite journal | vauthors = Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS | display-authors = 6 | title = Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma | journal = Journal of Clinical Oncology | volume = 33 | issue = 25 | pages = 2780–8 | date = September 2015 | pmid = 26014293 | doi = 10.1200/JCO.2014.58.3377 | doi-access = free }}</ref>

==Clinical significance==

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.<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 | s2cid = 169334 }}</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 | vauthors = Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, Weber-Carstens S, Hasper D, Keh D, Zuckermann H, Reinke P, Volk HD | display-authors = 6 | 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 = 640–8 | date = October 2009 | pmid = 19590022 | doi = 10.1164/rccm.200903-0363OC }}</ref> and [[neutrophil]]<ref>{{cite journal | vauthors = Pinder EM, Rostron AJ, Hellyer TP, Ruchaud-Sparagano MH, Scott J, Macfarlane JG, Wiscombe S, Widdrington JD, Roy AI, Linnett VC, Baudouin SV, Wright SE, Chadwick T, Fouweather T, Juss JK, Chilvers ER, Bowett SA, Parker J, McAuley DF, Conway Morris A, Simpson AJ | display-authors = 6 | title = Randomised controlled trial of GM-CSF in critically ill patients with impaired neutrophil phagocytosis | journal = Thorax | volume = 73 | issue = 10 | pages = 918–925 | date = October 2018 | pmid = 30064991 | pmc = 6166597 | doi = 10.1136/thoraxjnl-2017-211323 }}</ref> function, although the impact on patient outcomes is currently unclear and awaits larger studies.

GM-CSF stimulates [[monocyte]]s and [[macrophage]]s to produce pro-inflammatory cytokines, including [[CCL17]].<ref name="pmid33150139" /> Elevated GM-CSF has been shown to contribute to inflammation in [[inflammatory arthritis]], [[osteoarthritis]], [[colitis]] [[asthma]], [[obesity]], and [[Coronavirus disease 2019|COVID-19]].<ref name="pmid33150139" /><ref name=Thwaites>{{cite journal | vauthors = Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, Liew F, Russell CD, Moore SC, Fairfield C, Carter E, Abrams S, Short CE, Thaventhiran T, Bergstrom E, Gardener Z, Ascough S, Chiu C, Docherty AB, Hunt D, Crow YJ, Solomon T, Taylor GP, Turtle L, Harrison EM, Dunning J, Semple MG, Baillie JK, Openshaw PJ | display-authors = 6 | title = Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19 | journal = Science Immunology | volume = 6 | issue = 57 | pages = eabg9873 | date = March 2021 | pmid = 33692097 | doi = 10.1126/sciimmunol.abg9873|pmc=8128298 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Zhao Y, Kilian C, Turner JE, Bosurgi L, Roedl K, Bartsch P, Gnirck AC, Cortesi F, Schultheiß C, Hellmig M, Enk LU, Hausmann F, Borchers A, Wong MN, Paust HJ, Siracusa F, Scheibel N, Herrmann M, Rosati E, Bacher P, Kylies D, Jarczak D, Lütgehetmann M, Pfefferle S, Steurer S, Zur-Wiesch JS, Puelles VG, Sperhake JP, Addo MM, Lohse AW, Binder M, Huber S, Huber TB, Kluge S, Bonn S, Panzer U, Gagliani N, Krebs CF | display-authors = 6 | title = Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients | journal = Science Immunology | volume = 6 | issue = 56 | date = February 2021 | pmid = 33622974 | doi = 10.1126/sciimmunol.abf6692|pmc=8128299 | doi-access = free }}</ref>

==Clinical trials==

[[Monoclonal antibody|Monoclonal antibodies]] against GM-CSF are being used as treatment in clinical trials against [[rheumatoid arthritis]], [[ankylosing spondylitis]], and COVID-19.<ref name="pmid33150139">{{cite journal | vauthors = Lee KM, Achuthan AA, Hamilton JA | title = GM-CSF: A Promising Target in Inflammation and Autoimmunity | journal = ImmunoTargets and Therapy | volume = 9 | pages = 225–240 | year = 2020 | pmid = 33150139 | pmc = 7605919 | doi = 10.2147/ITT.S262566 | doi-access = free }}</ref>

== See also ==

* [[CFU-GM]]

* [[Filgrastim]] (Neupogen, a [[granulocyte colony-stimulating factor]] (G-CSF) analog)

* [[Granulocyte-macrophage colony-stimulating factor receptor]]

* [[Lenzilumab]]

* [[Pegfilgrastim]] (Neulasta, a [[PEGylated]] form [[filgrastim]])

== References ==

{{Reflist|32em}}

== External links ==

* [http://www.gm-csf.com/ Official gentaur web site]

* [http://www.leukine.com/ Official Leukine web site]

* {{MeshName|Granulocyte-Macrophage+Colony-Stimulating+Factor}}

* {{PDBe-KB2|P04141|Granulocyte-macrophage colony-stimulating factor}}

{{PDB Gallery|geneid=1437}}

{{Colony-stimulating factors}}

{{Cytokine receptor modulators}}

{{Portal bar|Biology}}

{{DEFAULTSORT:Granulocyte-macrophage colony-stimulating factor}}

[[Category:Cytokines]]

[[Category:Drugs acting on the blood and blood forming organs]]

[[Category:Growth factors]]