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]
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.
↑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. PMID10081506.
↑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.
↑Voehringer D (October 2012). "Basophil modulation by cytokine instruction". European Journal of Immunology. 42 (10): 2544–50. doi:10.1002/eji.201142318. PMID23042651.
↑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. PMID7493686.
↑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.
↑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. ISSN1535-4970. PMID19590022.
↑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. ISSN1468-3296. PMID30064991.
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