The role of TSG-6 and uroplakin III in bladder pain syndrome/ interstitial cystitis in rats and humans

Document Type : Original Article


1 Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China

2 Department of Emergency Medicine, Fujian Provincial Hospital, Fuzhou 350005, China


Objective(s):We investigated the relationship between the expression of tumor necrosis factor-inducible gene 6 (TSG-6) with inflammation and integrity of the bladder epithelium in the bladder tissues of patients with bladder pain syndrome/interstitial cystitis (BPS/IC) and the mechanism of action using a rat model of BPS/IC.  
Materials and Methods: Expression of TSG-6 and uroplakin III was determined by immuno- histochemistry of bladder biopsy samples from control human subjects and patients with verified BPS/IC. Our rat model of BPS/IC was employed to measure the perfusion of bladders with hyaluronidase, and assessment of the effect of TSG-6 administration on disease progression. Treatment effects were assessed by measurement of metabolic characteristics, RT-PCR of TGR-6 and interleukin-6, bladder histomorphology, and immunohistochemistry of TGR-6 and uroplakin III.
Results: The bladders of patients with BPS/IC had lower expression of uroplakin III and higher expression of TSG-6 than controls. Rats treated with hyaluronidase for 1 week developed the typical signs and symptoms of BPS/IC, and rats treated with hyaluronidase for 4 weeks had more serious disease. Administration of TSG-6 reversed the effects of hyaluronidase and protected against disease progression.
Conclusion:Our results indicate that TSG-6 plays an important role in maintaining the integrity of the bladder epithelial barrier.


1.Nordling J, Fall M, Hanno P. Global concepts of bladder pain syndrome (interstitial cystitis). World J Urol 2012; 30:457-464.
2.Lv YS, Yao YS, Lin ME, Rong L, Deng BH, Huang J, et al. Interleukin-6 levels in female rats with protamine sulfate-induced chronic cystitis treated with hyaluronic acid. Int J Urol 2013; 20:1017-1022.
3.Bassi, PF, Costantini, E, Foley,S, Palea, S. Glycosaminoglycan therapy for bladder diseases: Emerging new treatments. Eur Urol Suppl 2011; 10:451-459.
4.Anger JT, Zabihi N, Clemens JQ, Payne CK, Saigal CS, Rodriguez LV. Treatment choice, duration, and cost in patients with interstitial cystitis and painful bladder syndrome. Int Urogynecol J 2011; 22:395-400.
5.Gülpınar O, Kayis A, Suer E, Gokce MI, Guclu AG, Arikan N. Clinical comparision of intravesical hyaluronic acid and hyaluronic acid-chondroitin sulphate therapy for patients with bladder pain syndrome/interstitital cystitis. Can Urol Assoc J 2014; 8:E610-E614.
6.Lv YS, Zhou HL, Mao HP, Gao R, Wang YD, Xue XY. Intravesical hyaluronic acid and alkalinized lidocaine for the treatment of severe painful bladder syndrome/interstitial cystitis. Int Urogynecol J 2012; 23:1715-1720.
7.Nomiya A, Naruse T, Niimi A, Nishimatsu H, Kume H, Igawa Y, et al. On- and post-treatment symptom relief by repeated instillations of heparin and alkalized lidocaine in interstitial cystitis. Int J Urol 2013; 20:1118-1122.
8.Riedl C, Engelhardt P, Schwarz B. Treatment costs of bladder pain syndrome/interstitial cystitis in Austria: a pharmacoeconomic approach following current guidelines. Clin Drug Investig 2013; 33:737-742.
9.Wu EQ, Birnbaum H, Mareva M, Parece A, Huang Z, Mallett D, et al. Interstitial Cystitis: Cost, treatment and co-morbidities in an employed population. Pharmacoeconomics 2006; 24:55-65.
10.Madersbacher H, van Ophoven A, van Kerrebroeck PE. GAG layer replenishment therapy for chronic forms of cystitis with intravesical glycosaminoglycans--a review. Neurourol Urodyn 2013; 32:9-18.
11.GuhaSarkar S, Banerjee R. Intravesical drug delivery: Challenges, current status, opportunities and novel strategies. J Control Release 2010; 148:147-159.
12.Lv YS, Yao YS, Rong L, Lin ME, Deng BH, Xie Y, et al. Intravesical hyaluronidase causes chronic cystitis in a rat model: a potential model of bladder pain syndrome/interstitial cystitis. Int J Urol 2014; 21:601-607.
13. Slobodov G, Feloney M, Gran C, Kyker KD, Hurst RE, Culkin DJ. Abnormal expression of molecular markers for bladder impermeability and differentiation in the urothelium of patients with interstitial cystitis. J Urol 2004; 171:1554-1558.
14.Keay S, Leitzell S, Ochrzcin A, Clements G, Zhan M, Johnson D. A mouse model for interstitial cystitis/painful bladder syndrome based on APF inhibition of bladder epithelial repair: a pilot study. BMC Urol 2012; 12:17.
15.Lee TH, Wisniewski HG, Vilcek J. A novel secretory tumor necrosis factor-inducible protein (TSG-6) is a member of the family of hyaluronate binding proteins, closely related to the adhesion receptor CD44. J Cell Biol 1992; 116:545-557.
16.Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009; 5:54-63.
17.Roddy GW, Oh JY, Lee RH, Bartosh TJ, Ylostalo J, Coble K, et al. Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-alpha stimulated gene/protein 6. Stem Cells 2011; 29:1572-1579.
18.Lin QM, Zhao S, Zhou LL, Fang XS, Fu Y, Huang ZT. Mesenchymal stem cells transplantation suppresses inflammatory responses in global cerebral ischemia: contribution of TNF-alpha-induced protein 6. Acta Pharmacol Sin 2013; 34:784-792.
19.Milner CM, Day AJ. TSG-6: a multifunctional protein associated with inflammation. J Cell Sci 2003; 116:1863-1873.
20.Prockop DJ. Concise review: two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation. Stem Cells 2013; 31:2042-2046.
21.Lauer ME, Cheng G, Swaidani S, Aronica MA, Weigel PH, Hascall VC. Tumor necrosis factor-stimulated gene-6 (TSG-6) amplifies hyaluronan synthesis by airway smooth muscle cells. J Biol Chem 2013; 288:423-431.
22.Bárdos T, Kamath RV, Mikecz K, Glant TT. Anti-inflammatory and chondroprotective effect of TSG-6 (tumor necrosis factor-alpha-stimulated gene-6) in murine models of experimental arthritis. Am J Pathol 2001; 159:1711-1721.
23.Milner CM, Higman VA, Day AJ. TSG-6: a pluripotent inflammatory mediator? Biochem Soc Trans 2006; 34:446-450.
24.Liu Y, Zhang R, Yan K, Chen F, Huang W, Lv B, et al. Mesenchymal stem cells inhibit lipopolysaccharide-induced inflammatory responses of BV2 microglial cells through TSG-6. J Neuroinflammation 2014; 11:135.
25.Tuo J, Cao X, Shen D, Wang Y, Zhang J, Oh JY, et al. Anti-inflammatory recombinant TSG-6 stabilizes the progression of focal retinal degeneration in a murine model. J Neuroinflammation 2012; 9:59.
26.Guo P, Zhang SZ, He H, Zhu YT, Tseng SC. TSG-6 controls transcription and activation of matrix metalloproteinase 1 in conjunctivochalasis. Invest Ophthalmol Vis Sci 2012; 53:1372-1380.
27.Oh JY, Roddy GW, Choi H, Lee RH, Ylöstalo JH, Rosa RH Jr, et al. Anti-inflammatory protein TSG-6 reduces inflammatory damage to the cornea following chemical and mechanical injury. Proc Natl Acad Sci USA 2010; 107:16875-16880.
28.Watanabe J, Shetty AK, Hattiangady B, Kim DK, Foraker JE, Nishida H, et al. Administration of TSG-6 improves memory after traumatic brain injury in mice. Neurobiol Dis 2013; 59:86-99.
29.Foskett AM, Bazhanov N, Ti X, Tiblow A, Bartosh TJ, Prockop DJ. Phase-directed therapy: TSG-6 targeted to early inflammation improves bleomycin-injured lungs. Am J Physiol Lung Cell Mol Physiol 2014; 306:L120-L131.
30.Homma Y, Ueda T, Tomoe H, Lin AT, Kuo HC, Lee MH, et al. Clinical guidelines for interstitial cystitis and hypersensitive bladder syndrome. Int J Urol 2009; 16:597-615.
31.Kitta T, Tanaka H, Mitsui T, Moriya K, Nonomura K. Type 4 phosphodiesterase inhibitor suppresses experimental bladder inflammation. BJU Int 2008; 102:1472-1476.
32.Rajasekaran M, Stein P, Parsons CL. Toxic factors in human urine that injure urothelium. Int J Urol 2006; 13:409-414.
33.Soler R, Bruschini H, Freire MP, Alves MT, Srougi M, Ortiz V. Urine is necessary to provoke bladder inflammation in protamine sulfate induced urothelial injury. J Urol 2008; 180:1527-1531.
34.Danchuk S, Ylostalo JH, Hossain F, Sorge R, Ramsey A, Bonvillain RW, et al. Human multipotent stromal cells attenuate lipopolysaccharide-induced acute lung injury in mice via secretion of tumor necrosis factor-alpha-induced protein 6. Stem Cell Res Ther 2011; 2:27.
35. Nagyeri G, Radacs M, Ghassemi-Nejad S, Tryniszewska B, Olasz K, Hutas G, et al. TSG-6 protein, a negative regulator of inflammatory arthritis, forms a ternary complex with murine mast cell tryptases and heparin. J Biol Chem 2011; 286:23559-23569.