Macrophage colony-stimulating factor

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.[5]

CSF1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCSF1, CSF-1, MCSF, colony stimulating factor 1
External IDsOMIM: 120420 MGI: 1339753 HomoloGene: 7282 GeneCards: CSF1
Orthologs
SpeciesHumanMouse
Entrez

1435

12977

Ensembl

ENSG00000184371

ENSMUSG00000014599

UniProt

P09603

P07141

RefSeq (mRNA)

NM_172212
NM_000757
NM_172210
NM_172211

NM_001113529
NM_001113530
NM_007778

RefSeq (protein)

NP_000748
NP_757349
NP_757350
NP_757351

NP_001107001
NP_001107002
NP_031804

Location (UCSC)Chr 1: 109.91 – 109.93 MbChr 3: 107.65 – 107.67 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5]

Four transcript variants encoding three different isoforms (a proteoglycan, glycoprotein and cell surface protein)[6] have been found for this gene.[5]

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.[7] M-CSF affects macrophages and monocytes in several ways, including stimulating increased phagocytic and chemotactic activity, and increased tumour cell cytotoxicity.[8] 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.[9]

M-CSF released by osteoblasts (as a result of endocrine stimulation by parathyroid hormone) exerts paracrine effects on osteoclasts.[10] M-CSF binds to receptors on osteoclasts inducing differentiation, and ultimately leading to increased plasma calcium levels—through the resorption (breakdown) of bone. 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.[11]

Clinical significance

Locally produced M-CSF in the vessel wall contributes to the development and progression of atherosclerosis.[12]

M-CSF has been described to play a role in renal pathology including acute kidney injury and chronic kidney failure.[13][14] The chronic activation of monocytes can lead to multiple metabolic, hematologic and immunologic abnormalities in patients with chronic kidney failure.[13] In the context of acute kidney injury, M-CSF has been implicated in promoting repair following injury,[15] but also been described in an opposing role, driving proliferation of a pro-inflammatory macrophage phenotype.[16]

As a drug target

PD-0360324 and MCS110 are CSF1 inhibitors in clinical trials for some cancers.[17] See also CSF1R inhibitors.

Interactions

Macrophage colony-stimulating factor has been shown to interact with PIK3R2.[18]

References
  1. GRCh38: Ensembl release 89: ENSG00000184371 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000014599 - 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. "Entrez Gene: CSF1 colony stimulating factor 1 (macrophage)".
  6. Jang MH, Herber DM, Jiang X, Nandi S, Dai XM, Zeller G, Stanley ER, Kelley VR (September 2006). "Distinct in vivo roles of colony-stimulating factor-1 isoforms in renal inflammation". Journal of Immunology. 177 (6): 4055–63. doi:10.4049/jimmunol.177.6.4055. PMID 16951369.
  7. Stanley ER, Berg KL, Einstein DB, Lee PS, Pixley FJ, Wang Y, Yeung YG (January 1997). "Biology and action of colony--stimulating factor-1". Molecular Reproduction and Development. 46 (1): 4–10. doi:10.1002/(SICI)1098-2795(199701)46:1<4::AID-MRD2>3.0.CO;2-V. PMID 8981357. S2CID 20846803.
  8. Nemunaitis J (April 1993). "Macrophage function activating cytokines: potential clinical application". Critical Reviews in Oncology/Hematology. 14 (2): 153–71. doi:10.1016/1040-8428(93)90022-V. PMID 8357512.
  9. Fixe P, Praloran V (June 1997). "Macrophage colony-stimulating-factor (M-CSF or CSF-1) and its receptor: structure-function relationships". European Cytokine Network. 8 (2): 125–36. PMID 9262961.
  10. 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. PMC 5967329. PMID 29844945.
  11. Sapi E (January 2004). "The role of CSF-1 in normal physiology of mammary gland and breast cancer: an update". Experimental Biology and Medicine. 229 (1): 1–11. doi:10.1177/153537020422900101. PMID 14709771. S2CID 30541196.
  12. Rajavashisth T, Qiao JH, Tripathi S, Tripathi J, Mishra N, Hua M, Wang XP, Loussararian A, Clinton S, Libby P, Lusis A (June 1998). "Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor- deficient mice". The Journal of Clinical Investigation. 101 (12): 2702–10. doi:10.1172/JCI119891. PMC 508861. PMID 9637704.
  13. Le Meur Y, Fixe P, Aldigier JC, Leroux-Robert C, Praloran V (September 1996). "Macrophage colony stimulating factor involvement in uremic patients". Kidney International. 50 (3): 1007–12. doi:10.1038/ki.1996.402. PMID 8872977.
  14. 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. S2CID 38517528.
  15. Zhang MZ, Yao B, Yang S, Jiang L, Wang S, Fan X, Yin H, Wong K, Miyazawa T, Chen J, Chang I, Singh A, Harris RC (December 2012). "CSF-1 signaling mediates recovery from acute kidney injury". The Journal of Clinical Investigation. 122 (12): 4519–32. doi:10.1172/JCI60363. PMC 3533529. PMID 23143303.
  16. Cao Q, Wang Y, Zheng D, Sun Y, Wang C, Wang XM, Lee VW, Wang Y, Zheng G, Tan TK, Wang YM, Alexander SI, Harris DC (April 2014). "Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotype switch in vivo". Kidney International. 85 (4): 794–806. doi:10.1038/ki.2013.341. PMID 24048378.
  17. Interest Builds in CSF1R for Targeting Tumor Microenvironment
  18. Gout I, Dhand R, Panayotou G, Fry MJ, Hiles I, Otsu M, Waterfield MD (December 1992). "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. doi:10.1042/bj2880395. PMC 1132024. PMID 1334406.

Further reading
  • Macrophage+Colony-Stimulating+Factor at the US National Library of Medicine Medical Subject Headings (MeSH)
  • Overview of all the structural information available in the PDB for UniProt: P09603 (Macrophage colony-stimulating factor 1) at the PDBe-KB.
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