Granulocyte-macrophage colony-stimulating factor explained

Symbol:GM_CSF
Granulocyte-macrophage colony-stimulating factor
Pfam:PF01109
Pfam Clan:CL0053
Interpro:IPR000773
Prosite:PDOC00584
Scop:2gmf

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, enhancing 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.

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

Imlygic was approved by the US FDA in October 2015,[16] 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.[17]

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.[18] In critically ill patients GM-CSF has been trialled as a therapy for the immunosuppression of critical illness, and has shown promise restoring monocyte[19] and neutrophil[20] function, although the impact on patient outcomes is currently unclear and awaits larger studies.

GM-CSF stimulates monocytes and macrophages to produce pro-inflammatory cytokines, including CCL17. Elevated GM-CSF has been shown to contribute to inflammation in inflammatory arthritis, osteoarthritis, colitis asthma, obesity, and COVID-19.[21] [22]

Clinical trials

Monoclonal antibodies against GM-CSF are being used as treatment in clinical trials against rheumatoid arthritis, ankylosing spondylitis, and COVID-19.[23]

See also

External links

Notes and References

  1. Root RK, Dale DC . 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 . March 1999 . 10081506 . 10.1086/513857 . free .
  2. Francisco-Cruz A, Aguilar-Santelises M, Ramos-Espinosa O, Mata-Espinosa D, Marquina-Castillo B, Barrios-Payan J, Hernandez-Pando R . Granulocyte-macrophage colony-stimulating factor: not just another haematopoietic growth factor . Medical Oncology . 31 . 1 . 774 . January 2014 . 24264600 . 10.1007/s12032-013-0774-6 . 24452892 .
  3. Gasson JC . Molecular physiology of granulocyte-macrophage colony-stimulating factor . Blood . 77 . 6 . 1131–45 . March 1991 . 2001448 . 10.1182/blood.V77.6.1131.1131 . free .
  4. Voehringer D . Basophil modulation by cytokine instruction . European Journal of Immunology . 42 . 10 . 2544–50 . October 2012 . 23042651 . 10.1002/eji.201142318 . 23972211 . free .
  5. Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS . Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival . Immunity . 39 . 4 . 697–710 . October 2013 . 24138881 . 3841917 . 10.1016/j.immuni.2013.09.006 .
  6. Hansen PJ, Dobbs KB, Denicol AC . Programming of the preimplantation embryo by the embryokine colony stimulating factor 2 . Animal Reproduction Science . 149 . 1–2 . 59–66 . September 2014 . 24954585 . 10.1016/j.anireprosci.2014.05.017 .
  7. Bowers SR, Mirabella F, Calero-Nieto FJ, Valeaux S, Hadjur S, Baxter EW, Merkenschlager M, Cockerill PN . 6 . 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 . April 2009 . 19158269 . 2655614 . 10.1128/MCB.01411-08 .
  8. Web site: Entrez Gene: CSF2 colony stimulating factor 2 (granulocyte-macrophage) .
  9. Armitage JO . Emerging applications of recombinant human granulocyte-macrophage colony-stimulating factor . Blood . 92 . 12 . 4491–508 . December 1998 . 9845514 . 10.1182/blood.V92.12.4491 .
  10. Web site: Molgramostim. AdisInsight. 3 April 2018. en.
  11. Staff. Back to the Future: Original Liquid Leukine® Coming Soon. Oncology Business Review. May 2008. 2016-08-29. https://web.archive.org/web/20160825034301/https://obroncology.com/documents/OBR_may08_LEUKINE.pdf. 2016-08-25. dead.
  12. Hussein AM, Ross M, Vredenburgh J, Meisenberg B, Hars V, Gilbert C, Petros WP, Coniglio D, Kurtzberg J, Rubin P . 6 . 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 . November 1995 . 7493686 . 10.1111/j.1600-0609.1995.tb00713.x . 25424116 .
  13. Web site: Press release: Novartis Oncology sharpens focus on key growth drivers. Novartis via SEC Edgar. 30 October 2002.
  14. Web site: Scientific Conclusions and Grounds for Amendment of the Summary of Product Characteristics Presented by the EMEA. EMA CPMP. 27 June 2000.
  15. Web site: Bayer Healthcare Pharmaceuticals Plant, Snohomish County, Washington State . pharmaceutical-technology.com . 12 November 2011.
  16. Web site: IMLYGIC (talimogene laherparepvec) . U.S. Food & Drug Administration . fda.gov . 17 December 2019.
  17. 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 . 6 . Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma . Journal of Clinical Oncology . 33 . 25 . 2780–8 . September 2015 . 26014293 . 10.1200/JCO.2014.58.3377 . free .
  18. Deiß A, Brecht I, Haarmann A, Buttmann M . Treating multiple sclerosis with monoclonal antibodies: a 2013 update . Expert Review of Neurotherapeutics . 13 . 3 . 313–35 . March 2013 . 23448220 . 10.1586/ern.13.17 . 169334 .
  19. 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 . 6 . 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 . October 2009 . 19590022 . 10.1164/rccm.200903-0363OC .
  20. 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 . 6 . Randomised controlled trial of GM-CSF in critically ill patients with impaired neutrophil phagocytosis . Thorax . 73 . 10 . 918–925 . October 2018 . 30064991 . 6166597 . 10.1136/thoraxjnl-2017-211323 .
  21. 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 . 6 . Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19 . Science Immunology . 6 . 57 . eabg9873 . March 2021 . 33692097 . 10.1126/sciimmunol.abg9873. 8128298 . free .
  22. 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 . 6 . 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 . February 2021 . 33622974 . 10.1126/sciimmunol.abf6692. 8128299 . free .
  23. Lee KM, Achuthan AA, Hamilton JA . GM-CSF: A Promising Target in Inflammation and Autoimmunity . ImmunoTargets and Therapy . 9 . 225–240 . 2020 . 33150139 . 7605919 . 10.2147/ITT.S262566 . free .

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