Granulocyte-macrophage colony-stimulating factor

Last updated
CSF2
GMCSF Crystal Structure.rsh.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CSF2 , GMCSF, colony stimulating factor 2, CSF
External IDs OMIM: 138960 MGI: 1339752 HomoloGene: 600 GeneCards: CSF2
Orthologs
SpeciesHumanMouse
Entrez

1437

12981

Ensembl

ENSG00000164400

ENSMUSG00000018916

UniProt

P04141

P01587

RefSeq (mRNA)

NM_000758

NM_009969

RefSeq (protein)

NP_000749

NP_034099

Location (UCSC) Chr 5: 132.07 – 132.08 Mb Chr 11: 54.14 – 54.14 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Granulocyte-macrophage colony-stimulating factor
PDB 1csg EBI.jpg
three-dimensional structure of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM_CSF)
Identifiers
SymbolGM_CSF
Pfam PF01109
Pfam clan CL0053
InterPro IPR000773
PROSITE PDOC00584
SCOP2 2gmf / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Granulocyte-macrophage colony-stimulating factor
GMCSF Crystal Structure.rsh.png
Clinical data
ATC code
Identifiers
  • Human granulocyte macrophage colony stimulating factor
CAS Number
DrugBank
ChemSpider
  • none
Chemical and physical data
Formula C639H1006N168O196S8
Molar mass 14434.54 g·mol−1
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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.

Contents

Unlike granulocyte colony-stimulating factor, which specifically promotes neutrophil proliferation and maturation, GM-CSF affects more cell types, especially macrophages and eosinophils. [5]

Function

GM-CSF is a monomeric glycoprotein that functions as a cytokine—it is a white blood cell growth factor. [6] 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.[ citation needed ]

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]

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. [11] Other genes in the cluster include those encoding interleukins 4, 5, and 13. [12]

Glycosylation

Human granulocyte-macrophage colony-stimulating factor is glycosylated in its mature form.[ citation needed ]

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. [13]

At that time, Genetics Institute, Inc. was working on molgramostim, [14] Immunex was working on sargramostim (Leukine), [15] and Sandoz was working on regramostim. [16]

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 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. [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.

GM-CSF stimulates monocytes and macrophages to produce pro-inflammatory cytokines, including CCL17. [25] Elevated GM-CSF has been shown to contribute to inflammation in inflammatory arthritis, osteoarthritis, colitis asthma, obesity, and COVID-19. [25] [26] [27]

Clinical trials

Monoclonal antibodies against GM-CSF are being used as treatment in clinical trials against rheumatoid arthritis, ankylosing spondylitis, and COVID-19. [25]

See also

Related Research Articles

A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.

<span class="mw-page-title-main">Granulocyte colony-stimulating factor</span> Mammalian protein found in Homo sapiens

Granulocyte colony-stimulating factor, also known as colony-stimulating factor 3, is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.

Interleukins (ILs) are a group of cytokines that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related proteins.

<span class="mw-page-title-main">Interleukin 3</span> Protein-coding gene in the species Homo sapiens

Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3 gene localized on chromosome 5q31.1. Sometimes also called colony-stimulating factor, multi-CSF, mast cell growth factor, MULTI-CSF, MCGF; MGC79398, MGC79399: the protein contains 152 amino acids and its molecular weight is 17 kDa. IL-3 is produced as a monomer by activated T cells, monocytes/macrophages and stroma cells. The major function of IL-3 cytokine is to regulate the concentrations of various blood-cell types. It induces proliferation and differentiation in both early pluripotent stem cells and committed progenitors. It also has many more specific effects like the regeneration of platelets and potentially aids in early antibody isotype switching.

<span class="mw-page-title-main">Interleukin 8</span> Mammalian protein found in Homo sapiens

Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel-Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.


Interleukin 5 (IL5) is an interleukin produced by type-2 T helper cells and mast cells.

Hemopoietic growth factors regulate the differentiation and proliferation of particular progenitor cells. Made available through recombinant DNA technology, they hold tremendous potential for medical uses when a person's natural ability to form blood cells is diminished or defective. Recombinant erythropoietin (EPO) is very effective in treating the diminished red blood cell production that accompanies end-stage kidney disease. Erythropoietin is a sialoglycoprotein hormone produced by peritubular cells of kidney.

Sargramostim is a recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) that functions as an immunostimulator.

<span class="mw-page-title-main">Macrophage colony-stimulating factor</span> Mammalian protein found in Homo sapiens

The colony stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF), is a secreted cytokine which causes hematopoietic stem cells to differentiate into macrophages or other related cell types. Eukaryotic cells also produce M-CSF in order to combat intercellular viral infection. It is one of the three experimentally described colony-stimulating factors. M-CSF binds to the colony stimulating factor 1 receptor. It may also be involved in development of the placenta.

<span class="mw-page-title-main">Granulopoiesis</span> Part of haematopoiesis, that leads to the production of granulocytes

Granulopoiesis is a part of haematopoiesis, that leads to the production of granulocytes. A granulocyte, also referred to as a polymorphonuclear leukocyte (PMN), is a type of white blood cell that has multi lobed nuclei, usually containing three lobes, and has a significant amount of cytoplasmic granules within the cell. Granulopoiesis takes place in the bone marrow. It leads to the production of three types of mature granulocytes: neutrophils, eosinophils and basophils.

Interleukin 27 (IL-27) is a member of the IL-12 cytokine family. It is a heterodimeric cytokine that is encoded by two distinct genes, Epstein-Barr virus-induced gene 3 (EBI3) and IL-27p28. IL-27 is expressed by antigen presenting cells and interacts with a specific cell-surface receptor complex known as IL-27 receptor (IL-27R). This receptor consists of two proteins, IL-27Rɑ and gp130. IL-27 induces differentiation of the diverse populations of T cells in the immune system and also upregulates IL-10.

<span class="mw-page-title-main">CXCL5</span> Mammalian protein found in Homo sapiens

C-X-C motif chemokine 5 is a protein that in humans is encoded by the CXCL5 gene.

<span class="mw-page-title-main">Granulocyte colony-stimulating factor receptor</span> Protein-coding gene in the species Homo sapiens

The granulocyte colony-stimulating factor receptor (G-CSF-R) also known as CD114 is a protein that in humans is encoded by the CSF3R gene. G-CSF-R is a cell-surface receptor for the granulocyte colony-stimulating factor (G-CSF). The G-CSF receptors belongs to a family of cytokine receptors known as the hematopoietin receptor family. The granulocyte colony-stimulating factor receptor is present on precursor cells in the bone marrow, and, in response to stimulation by G-CSF, initiates cell proliferation and differentiation into mature neutrophilic granulocytes and macrophages.

<span class="mw-page-title-main">G-CSF factor stem-loop destabilising element</span> RNA element

The G-CSF factor stem-loop destabilising element (SLDE) is an RNA element secreted by fibroblasts and endothelial cells in response to the inflammatory mediators interleukin-1 (IL-1) and tumour necrosis factor-alpha and by activated macrophages. The synthesis of G-CSF is regulated both transcriptionally and through control of mRNA stability. In unstimulated cells G-CSF mRNA is unstable but becomes stabilised in response to IL-1 or tumour necrosis factor alpha, and also in the case of monocytes and macrophages, in response to lipopolysaccharide. It is likely that the presence of the SLDE in the G-CSF mRNA contributes to the specificity of regulation of G-CSF mRNA and enhances the rate of shortening of the poly(A) tail.

<span class="mw-page-title-main">Granulocyte-macrophage colony-stimulating factor receptor</span> Protein-coding gene in humans

The granulocyte-macrophage colony-stimulating factor receptor also known as CD116, is a receptor for granulocyte-macrophage colony-stimulating factor, which stimulates the production of white blood cells. In contrast to M-CSF and G-CSF which are lineage specific, GM-CSF and its receptor play a role in earlier stages of development. The receptor is primarily located on neutrophils, eosinophils and monocytes/macrophages, it is also on CD34+ progenitor cells (myeloblasts) and precursors for erythroid and megakaryocytic lineages, but only in the beginning of their development.

The interleukin-5 receptor is a type I cytokine receptor. It is a heterodimer of the interleukin 5 receptor alpha subunit and CSF2RB.

<span class="mw-page-title-main">CFU-GEMM</span>

CFU-GEMM is a colony forming unit that generates myeloid cells. CFU-GEMM cells are the oligopotential progenitor cells for myeloid cells; they are thus also called common myeloid progenitor cells or myeloid stem cells. "GEMM" stands for granulocyte, erythrocyte, monocyte, megakaryocyte.

<span class="mw-page-title-main">Talimogene laherparepvec</span> Gene therapy medication

Talimogene laherparepvec, sold under the brand name Imlygic, is a biopharmaceutical medication used to treat melanoma that cannot be operated on; it is injected directly into a subset of lesions which generates a systemic immune response against the recipient's cancer. The final four year analysis from the pivotal phase 3 study upon which TVEC was approved by the FDA showed a 31.5% response rate with a 16.9% complete response (CR) rate. There was also a substantial and statistically significant survival benefit in patients with earlier metastatic disease and in patients who hadn't received prior systemic treatment for melanoma. The earlier stage group had a reduction in the risk of death of approximately 50% with one in four patients appearing to have met, or be close to be reaching, the medical definition of cure. Real world use of talimogene laherparepvec have shown response rates of up to 88.5% with CR rates of up to 61.5%.

Lenzilumab is a humanized monoclonal antibody that targets colony stimulating factor 2 (CSF2)/granulocyte-macrophage colony stimulating factor (GM-CSF).

Otilimab is a fully human antibody which has been developed by the biotechnology company MorphoSys. It can also be referred to as HuCAL antibody, HuCAL standing for Human Combinatorial Antibody Library and being a technology used to generate monoclonal antibodies. Otilimab is directed against the granulocyte-macrophage colony stimulating factor (GM-CSF), a monomeric glycoprotein functioning as a cytokine promoting both proliferation and activation of macrophages and neutrophils.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000164400 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000018916 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ Gasson JC (March 1991). "Molecular physiology of granulocyte-macrophage colony-stimulating factor". Blood. 77 (6): 1131–45. doi: 10.1182/blood.V77.6.1131.1131 . PMID   2001448.
  8. ↑ Voehringer D (October 2012). "Basophil modulation by cytokine instruction". European Journal of Immunology. 42 (10): 2544–50. doi: 10.1002/eji.201142318 . PMID   23042651. S2CID   23972211.
  9. ↑ Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS (October 2013). "Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival". Immunity. 39 (4): 697–710. doi:10.1016/j.immuni.2013.09.006. PMC   3841917 . PMID   24138881.
  10. ↑ 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.
  11. ↑ 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. PMC   2655614 . PMID   19158269.
  12. ↑ "Entrez Gene: CSF2 colony stimulating factor 2 (granulocyte-macrophage)".
  13. ↑ 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.
  14. ↑ "Molgramostim". AdisInsight. Retrieved 3 April 2018.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ "Press release: Novartis Oncology sharpens focus on key growth drivers". Novartis via SEC Edgar. 30 October 2002.
  18. ↑ "Scientific Conclusions and Grounds for Amendment of the Summary of Product Characteristics Presented by the EMEA" (PDF). EMA CPMP. 27 June 2000.
  19. ↑ "Bayer Healthcare Pharmaceuticals Plant, Snohomish County, Washington State". pharmaceutical-technology.com. Retrieved 12 November 2011.
  20. ↑ U.S. Food & Drug Administration. "IMLYGIC (talimogene laherparepvec)". fda.gov. Retrieved 17 December 2019.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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. PMC   6166597 . PMID   30064991.
  25. 1 2 3 Lee 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 . PMC   7605919 . PMID   33150139.
  26. ↑ 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 . PMC   8128298 . PMID   33692097.
  27. ↑ 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 . PMC   8128299 . PMID   33622974.
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