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CSF2

Official Full Name
colony stimulating factor 2
Organism
Homo sapiens
GeneID
1437
Background
The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of granulocytes and macrophages. The active form of the protein is found extracellularly as a homodimer. This 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. Other genes in the cluster include those encoding interleukins 4, 5, and 13. This gene plays a role in promoting tissue inflammation. Elevated levels of cytokines, including the one produced by this gene, have been detected in SARS-CoV-2 infected patients that develop acute respiratory distress syndrome. Mice deficient in this gene or its receptor develop pulmonary alveolar proteinosis. [provided by RefSeq, Aug 2020]
Synonyms
CSF; GMCSF;
Bio Chemical Class
Growth factor
Protein Sequence
MWLQSLLLLGTVACSISAPARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDLQEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKENLKDFLLVIPFDCWEPVQE
Open
Disease
Asthma, Colorectal cancer, COVID-19, Diabetes mellitus, Liver cancer, Melanoma, Myeloproliferative neoplasm, Pancreatic cancer, Prostate cancer, Psoriasis, Rheumatoid arthritis, Solid tumour/cancer
Approved Drug
1 +
Clinical Trial Drug
12 +
Discontinued Drug
1 +

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Detailed Information

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), encoded by the CSF2 gene, is a crucial cytokine that plays a vital role in the development of the immune system, differentiation of immune cells, and immune responses. First found for its function in hematopoiesis, GM-CSF helps bone marrow stem cells differentiate into granulocytes and macrophages. More investigation has shown its important involvement in immunological reactivity, disease processes, immune development, and certain clinical diseases as well as in immune development.

Molecular Mechanism and Receptor Structure of GM-CSF

GM-CSF operates in an active state as a dimer, engaging with certain cell surface receptors to produce biological effects. Comprising an α chain liable for ligand binding and a β chain for signal transmission, the GM-CSF receptor (GM-CSFR) is a heterodimer. Although it lacks natural tyrosine kinase activity, the β chain notably exhibits signaling characteristics with the interleukin-3 (IL-3) and IL-5 receptors.

Receptor aggregation results from GM-CSF binding to its receptor, therefore activating JAK2 tyrosine kinase linked to the β chain. Tyrosine residues on the receptor phosphorylated by JAK2 activation recruit and activate transcription factors such as STAT5, hence starting the JAK-STAT cascade. Through the PI3K-Akt and MAPK signaling pathways, GM-CSF may also control cell proliferation, differentiation, and survival, thereby profoundly affecting the roles of macrophages, granulocytes, dendritic cells, and other immune cells.

Figure 1 illustrates the GM-CSF receptor and its associated signaling pathways, detailing how GM-CSF interacts with its receptor to activate downstream cellular processes.Figure 1. Diagram of the GM-CSF receptor and its signaling pathway. (Chen Y, Li F, et al., 2023)

Role of GM-CSF in Immune Cell Production and Function

Promoting the development of bone marrow stem cells into granulocytes and macrophages—critical for the immunological defense of the host—is GM-CSF's main goal. The initial line of protection for the body is formed by granulocytes, macrophages, and other immune cells that quickly detect and destroy invading germs.

Development of Macrophages and Granulocytes

By upregulating transcription factor PU.1 and therefore aiding their differentiation and functional maturation, GM-CSF is essential for macrophage development. Through cytokine and chemokine release, macrophages control local immunological reactions and function as "cleaners" in immune responses. GM-CSF also boosts granulocyte production, especially neutrophils, which are vital in acute inflammatory reactions.

Regulation of Immune Responses by GM-CSF

Beyond hematopoiesis, GM-CSF is very essential in controlling immune responses. It controls immune cell function, therefore improving their cytotoxic power and encouraging their movement and gathering. GM-CSF improves dendritic cell growth and function, for example, by processing and presenting antigens, activating T cells, and starting certain immunological reactions, therefore affecting adaptive immune responses.

GM-CSF's Relationship with Various Diseases

1. GM-CSF in Respiratory Illnesses

Particularly in pulmonary alveolar proteinosis (PAP), a rare lung condition, GM-CSF is very crucial for lung health. Mostly owing to GM-CSF malfunction, which causes significant pulmonary problems, PAP is defined by surfactant buildup and compromised macrophage activity. Emphasizing its critical significance in maintaining alveolar macrophage activity and removing surfactants, research has demonstrated that mice devoid of GM-CSF or its receptor are prone to develop PAP.

Furthermore, under focus is GM-CSF's contribution to acute respiratory distress syndrome (ARS), particularly in severe COVID-19 patients. Cytokine storms and abrupt respiratory failure are associated with increased GM-CSF levels. Although GM-CSF first aids in macrophage clearance of infections, it may aggravate immune responses and lead to tissue damage in acute inflammation.

2. GM-CSF for Autoimmune Conditions

Deeply engaged in autoimmune illnesses like rheumatoid arthritis (RA) and multiple sclerosis (MS), GM-CSF is GM-CSF levels increase in synovial regions in RA, stimulating T cells and macrophages to magnify local inflammation. GM-CSF also stimulates leukocyte invasion and macrophage activity in MS, which helps to cause nerve demyelination. Its part in causing inflammation makes it a main target of therapeutic intervention in autoimmune diseases.

3. GM-CSF in allergic disorders

Particularly for asthma, GM-CSF has a big influence on allergic disorders. It increases the survival and activity of eosinophils, therefore aggravating persistent airway inflammation. Targeting GM-CSF pathways or reducing its activity offers a possible strategy to control allergic responses and inflammation in asthma and allied disorders.

4. GM-CSF in diseases including inflammatory bowel disease (IBD).

In IBD, particularly Crohn's disease (CD) and ulcerative colitis (UC), which are characterized by persistent intestinal inflammation, GM-CSF is essential. It stimulates immune cell activation, therefore supporting the inflammatory process in the intestines. While recombinant GM-CSF treatment has shown potential in reducing CD symptoms, studies have demonstrated that inhibiting GM-CSF may help animal models with colitis. These results underline GM-CSF as a possible treatment target and instrument for IBD control.

5. GM-CSF Regarding Cancer

GM-CSF has a multifarious and two-edged involvement in cancer. It is a focus of cancer immunotherapy as, on one side, it displays anticancer promise by increasing immune identification and tumor cell clearance. In certain malignancies, however, tumor-secreted GM-CSF may promote development and spread. Rising tumor invasiveness in colorectal, bladder, and glioblastoma tumors is linked to high GM-CSF levels. Developing successful cancer treatments still depends much on balancing the expression and activity of GM-CSF.

6. Wound Healing

Wound healing depends on GM-CSF, however, in diabetes individuals, its signaling flaws often slow down the process. By improving macrophage activity, removing dead tissue, and encouraging the production of growth factors, studies on augmenting GM-CSF in diabetic mice have demonstrated that this improves wound healing. This emphasizes its possibilities as a therapeutic tool for enhancing results of tissue healing and restoration.

References:

  1. Cai H, Zhang Y, Wang J, et al. Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1. Front Immunol. 2021 Jun 23;12:690869.
  2. Hamilton JA. GM-CSF in inflammation. J Exp Med. 2020 Jan 6;217(1):e20190945.
  3. Chen Y, Li F, et al. Role of GM-CSF in lung balance and disease. Front Immunol. 2023;14:1158859.
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