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Altered expression of bladder mast cell growth factor receptor (c-kit) in interstitial cystitis
X Pang1, G Sant, T C Theoharides
1Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, New England Medical Center, Boston, Massachusetts 02111, USA.
Insights
Interstitial cystitis (IC) patients show increased bladder mast cells, but these cells have reduced surface c-kit receptors. This suggests mast cell activation in IC may be driven by stem cell factor (SCF) binding to c-kit.
Area of Science:
- Urology
- Immunology
- Cell Biology
Background:
- Interstitial cystitis (IC) is a chronic bladder condition primarily affecting women, characterized by pain, urgency, and frequency.
- A leading theory suggests increased and activated bladder mast cells contribute to IC pathophysiology.
- Stem cell factor (SCF), also known as c-kit ligand, is crucial for mast cell proliferation via its receptor, c-kit.
Purpose of the Study:
- To investigate the expression of mast cell growth factor receptors (c-kit) on bladder mast cells in patients with interstitial cystitis (IC).
Main Methods:
- Bladder specimens from IC patients and controls were obtained during cystoscopy.
- Immunohistochemistry was used to detect tryptase (a mast cell enzyme) and c-kit expression.
Main Results:
- IC patients exhibited a higher number of bladder mast cells compared to controls.
- Mast cells in IC patients showed reduced surface expression of c-kit compared to controls.
- This reduction may be due to c-kit being occupied by SCF or downregulated after ligand binding.
Conclusions:
- Increased mast cell numbers and/or activation in a subset of IC patients may result from elevated SCF stimulation.
- This could be due to c-kit mutations causing constitutive activation or SCF overproduction leading to mast cell proliferation in IC.
Objectives:
To investigate the presence of mast cell growth factor receptors (c-kit) on bladder mast cells in interstitial cystitis (IC), a bladder condition occurring primarily in women. IC is characterized by pain, urgency, frequency, and mucosal microhemorrhages discernible with cystoscopy under general anesthesia. One of the prevailing theories to explain IC pathophysiology is the increased number of bladder mast cells, many of which are activated in at least a subgroup of IC patients. Stem cell factor (SCF), also known as c-kit ligand, is now recognized as the key molecule responsible for mast cell proliferation and is known to exert its action through specific surface receptors.
Methods:
Bladder specimens from patients with IC, identified by the criteria established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and control patients were obtained during diagnostic cystoscopy and were immediately fixed in 4% paraformaldehyde. They were then examined by immunohistochemistry for the unique proteolytic mast cell enzyme tryptase or the presence of c-kit, or both.
Results:
Bladders of IC patients contained a higher number of mast cells than control patients. However, mast cells in IC patients expressed fewer c-kit on their surface than those in control patients. These results could be explained if the c-kit were occupied by endogenous SCF or were downregulated, possibly by internalization after ligand-receptor interactions, making them inaccessible to immunocytochemical detection.
Conclusions:
Bladder mastocytosis and/or activation of mast cells, in at least a subpopulation of IC patients, may be explained by increased stimulation of mast cells by SCF. These results could be explained either by a mutation leading to constitutive activation of c-kit or overproduction of c-kit ligand leading to bladder mast cell proliferation in IC.