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.[citation needed]
GM-CSF also plays a role in embryonic development by functioning as an embryokine produced by reproductive tract.[10]
Geneticsedit
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]
Glycosylationedit
Human granulocyte-macrophage colony-stimulating factor is glycosylated in its mature form.[citation needed]
Historyedit
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]
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 was subsequently 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]
Clinical significanceedit
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.
^ abcGRCh38: Ensembl release 89: ENSG00000164400 – Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000018916 – Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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. PMID 10081506.
^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. S2CID 24452892.
^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.
^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. PMID 19158269.
^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.
^"Molgramostim". AdisInsight. Retrieved 3 April 2018.
^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.
^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. PMID 7493686. S2CID 25424116.
^"Press release: Novartis Oncology sharpens focus on key growth drivers". Novartis via SEC Edgar. 30 October 2002.
^"Scientific Conclusions and Grounds for Amendment of the Summary of Product Characteristics Presented by the EMEA" (PDF). EMA CPMP. 27 June 2000.
^"Bayer Healthcare Pharmaceuticals Plant, Snohomish County, Washington State". pharmaceutical-technology.com. Retrieved 12 November 2011.
^U.S. Food & Drug Administration. "IMLYGIC (talimogene laherparepvec)". fda.gov. Retrieved 17 December 2019.
^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. PMID 26014293.
^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. S2CID 169334.
^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. PMID 19590022.
^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. PMID 30064991.
^ 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. PMID 33150139.
^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. PMID 33692097.
^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. PMID 33622974.
External linksedit
Official gentaur web site
Official Leukine web site
Granulocyte-Macrophage+Colony-Stimulating+Factor at the U.S. 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.