Biology:Macrophage colony-stimulating factor

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Short description: Mammalian protein found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.[1]

Structure

M-CSF is a cytokine, being a smaller protein involved in cell signaling. The active form of the protein is found extracellularly as a disulfide-linked homodimer, and is thought to be produced by proteolytic cleavage of membrane-bound precursors.[1]

Four transcript variants encoding three different isoforms (a proteoglycan, glycoprotein and cell surface protein)[2] have been found for this gene.[1]

Function

M-CSF (or CSF-1) is a hematopoietic growth factor that is involved in the proliferation, differentiation, and survival of monocytes, macrophages, and bone marrow progenitor cells.[3] M-CSF affects macrophages and monocytes in several ways, including stimulating increased phagocytic and chemotactic activity, and increased tumour cell cytotoxicity.[4] The role of M-CSF is not only restricted to the monocyte/macrophage cell lineage. By interacting with its membrane receptor (CSF1R or M-CSF-R encoded by the c-fms proto-oncogene), M-CSF also modulates the proliferation of earlier hematopoietic progenitors and influence numerous physiological processes involved in immunology, metabolism, fertility and pregnancy.[5]

M-CSF released by osteoblasts (as a result of endocrine stimulation by parathyroid hormone) exerts paracrine effects on osteoclasts.[6] M-CSF binds to receptors on osteoclasts inducing differentiation, and ultimately leading to increased plasma calcium levels—through the resorption (breakdown) of bone[citation needed]. Additionally, high levels of CSF-1 expression are observed in the endometrial epithelium of the pregnant uterus as well as high levels of its receptor CSF1R in the placental trophoblast. Studies have shown that activation of trophoblastic CSF1R by local high levels of CSF-1 is essential for normal embryonic implantation and placental development. More recently, it was discovered that CSF-1 and its receptor CSF1R are implicated in the mammary gland during normal development and neoplastic growth.[7]

Clinical significance

Locally produced M-CSF in the vessel wall contributes to the development and progression of atherosclerosis.[8]

M-CSF has been described to play a role in renal pathology including acute kidney injury and chronic kidney failure.[9][10] The chronic activation of monocytes can lead to multiple metabolic, hematologic and immunologic abnormalities in patients with chronic kidney failure.[9] In the context of acute kidney injury, M-CSF has been implicated in promoting repair following injury,[11] but also been described in an opposing role, driving proliferation of a pro-inflammatory macrophage phenotype.[12]

As a drug target

PD-0360324 and MCS110 are CSF1 inhibitors in clinical trials for some cancers.[13] See also CSF1R inhibitors.

Interactions

Macrophage colony-stimulating factor has been shown to interact with PIK3R2.[14]

References

  1. 1.0 1.1 1.2 "Entrez Gene: CSF1 colony stimulating factor 1 (macrophage)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1435. 
  2. "Distinct in vivo roles of colony-stimulating factor-1 isoforms in renal inflammation". Journal of Immunology 177 (6): 4055–63. September 2006. doi:10.4049/jimmunol.177.6.4055. PMID 16951369. 
  3. "Biology and action of colony--stimulating factor-1". Molecular Reproduction and Development 46 (1): 4–10. January 1997. doi:10.1002/(SICI)1098-2795(199701)46:1<4::AID-MRD2>3.0.CO;2-V. PMID 8981357. 
  4. "Macrophage function activating cytokines: potential clinical application". Critical Reviews in Oncology/Hematology 14 (2): 153–71. April 1993. doi:10.1016/1040-8428(93)90022-V. PMID 8357512. 
  5. "Macrophage colony-stimulating-factor (M-CSF or CSF-1) and its receptor: structure-function relationships". European Cytokine Network 8 (2): 125–36. June 1997. PMID 9262961. http://www.jle.com/fr/revues/ecn/e-docs/macrophage_colony_stimulating_factor_m_csf_or_csf_1_and_its_receptor_structure_function_relationships_90247/article.phtml?tab=texte. 
  6. Han, Yujiao; You, Xiuling; Xing, Wenhui; Zhang, Zhong; Zou, Weiguo (2018). "Paracrine and endocrine actions of bone—the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts". Bone Research 6: 16. doi:10.1038/s41413-018-0019-6. PMID 29844945. 
  7. "The role of CSF-1 in normal physiology of mammary gland and breast cancer: an update". Experimental Biology and Medicine 229 (1): 1–11. January 2004. doi:10.1177/153537020422900101. PMID 14709771. 
  8. "Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor- deficient mice". The Journal of Clinical Investigation 101 (12): 2702–10. June 1998. doi:10.1172/JCI119891. PMID 9637704. 
  9. 9.0 9.1 "Macrophage colony stimulating factor involvement in uremic patients". Kidney International 50 (3): 1007–12. September 1996. doi:10.1038/ki.1996.402. PMID 8872977. 
  10. Lim, G. B. (2013-01-01). "Acute kidney injury: CSF-1 signalling is involved in repair following AKI". Nature Reviews Nephrology 9 (1): 2. doi:10.1038/nrneph.2012.253. ISSN 1759-5061. PMID 23165301. 
  11. "CSF-1 signaling mediates recovery from acute kidney injury". The Journal of Clinical Investigation 122 (12): 4519–32. December 2012. doi:10.1172/JCI60363. PMID 23143303. 
  12. "Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotype switch in vivo". Kidney International 85 (4): 794–806. April 2014. doi:10.1038/ki.2013.341. PMID 24048378. 
  13. Interest Builds in CSF1R for Targeting Tumor Microenvironment
  14. "Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 beta protein by using the baculovirus expression system". The Biochemical Journal 288 (2): 395–405. December 1992. doi:10.1042/bj2880395. PMID 1334406. 

Further reading

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