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 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 interleukins 4, 5, and 13.[7]
Glycosylation
Human granulocyte-macrophage colony-stimulating factor is glycosylated in its mature form.
GM-CSF has also been evaluated in clinical trials for its potential as a vaccine adjuvant in HIV-infected patients.[9][10]
Sargramostim
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;[11]Immunex developed GM-CSF manufactured in yeast into sargramostim ( Leukine).[12] Clinical trials of sargramostim were initiated in 1987;[13] 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.[14]
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.[15] In November 1996, the FDA also approved sargramostim for treatment of fungal infections and replenishment of white blood cells following chemotherapy.[16] A liquid formulation was approved in 1995.[12] Immunex was acquired by Amgen in 2002.[13] As part of the acquisition, Leukine was spun off to Berlex, which became Bayer HealthCare in 2007.[12] In 2009, Genzyme acquired the rights to Leukine from Bayer, including the manufacturing facility in the Seattle area.[13][17][18]
Rheumatoid arthritis
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.[19]
↑Root RK, Dale DC (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): S342–352. PMID10081506.
↑Francisco-Cruz A, Aguilar-Santelises M, Ramos-Espinosa O, Mata-Espinosa D, Marquina-Castillo B, Barrios-Payan J, Hernandez-Pando R (Jan 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 (Oct 2012). "Basophil modulation by cytokine instruction". European Journal of Immunology. 42 (10): 2544–50. doi:10.1002/eji.201142318. PMID23042651.
↑"Approval Summary for sargramostim". Oncology Tools. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. 1991-03-05. Archived from the original on 24 June 2007. Retrieved 20 September 2009.
↑Deiß A, Brecht I, Haarmann A, Buttmann M (Mar 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.
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