Rapamycin‑induced autophagy attenuates hormone‑imbalance‑induced chronic non‑bacterial prostatitis in rats via the inhibition of NLRP3 inflammasome‑mediated inflammation

Lu,Jingxiao; Su,Yang; Chen,Xianguo; Chen,Yuan; Luo,Pengcheng; Lin,Fangyou; Zhang,Jie

doi:10.3892/mmr.2018.9683

Rapamycin‑induced autophagy attenuates hormone‑imbalance‑induced chronic non‑bacterial prostatitis in rats via the inhibition of NLRP3 inflammasome‑mediated inflammation

Authors:
- Jingxiao Lu
- Yang Su
- Xianguo Chen
- Yuan Chen
- Pengcheng Luo
- Fangyou Lin
- Jie Zhang
View Affiliations

Affiliations: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China, Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Clinical Laboratory, Children and Women Hospital of Edong Health Group, Huangshi, Hubei 435000, P.R. China, Department of Urology, Huangshi Central Hospital, Hubei Polytechnic University, Huangshi, Hubei 435000, P.R. China
Published online on: November 21, 2018 https://doi.org/10.3892/mmr.2018.9683
Pages: 221-230
Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Chronic non‑bacterial prostatitis (CNBP) is a common urinary disease and no standard treatments are available at present. Although autophagy serves an important role in a variety of chronic diseases, its role in CNBP is yet to be fully elucidated. Therefore, the present study aimed to investigate the effects of rapamycin‑induced autophagy on CNBP by establishing a rat model. In the present study, a total of 30 male Sprague‑Dawley rats were randomly divided into three groups (n=10 per group): i) Control, in which rats underwent a sham operation; ii) the model (CNBP), in which rats were castrated and administered 17β‑estradiol (0.25 mg/kg via subcutaneous injection) for 30 consecutive days; and iii) rapamycin treatment, in which rats were employed in accordance with the CNBP model, but also received a daily intraperitoneal injection of rapamycin (1 mg/kg) from the 16th day post‑surgery for 15 days. Alterations in histology and the levels of autophagy‑associated markers, and components of the NLRP3 inflammasome, were measured in the prostate tissues of the rats. The levels of molecules located further downstream of the NLRP3 inflammasome pathway, including interleukin (IL)‑1β and IL‑18, were also measured. The results demonstrated that, compared with the control group, increased infiltration levels of inflammatory cells and glandular epithelial degeneration were observed in the prostate tissues of rats with CNBP. Furthermore, a significant increase in the concentration of IL‑1β and IL‑18 in the serum, as well as the increased expression levels of NLRP3, ASC and caspase‑1 in prostate tissues were also observed. In addition, reductions in the number of autophagosomes and the expression levels of autophagy‑associated, including microtubule‑associated protein 1 light chain 3β (LC3B) and Beclin 1, were also detected in the CNBP group; however, treatment with rapamycin reversed these effects. Collectively, the findings of the present study indicated that the NLRP3 inflammasome‑mediated inflammatory response was activated by a hormonal imbalance in the prostate glands of rats; however, these effects may be suppressed via rapamycin‑induced autophagy.

View Figures

View References

1	Ellem SJ, Wang H, Poutanen M and Risbridger GP: Increased endogenous estrogen synthesis leads to the sequential induction of prostatic inflammation (prostatitis) and prostatic pre-malignancy. Am J Pathol. 175:1187–1199. 2009. View Article : Google Scholar : PubMed/NCBI
2	Krieger JN, Lee SW, Jeon J, Cheah PY, Liong ML and Riley DE: Epidemiology of prostatitis. Int J Antimicrob Agents. 31 Suppl 1:S85–S90. 2008. View Article : Google Scholar : PubMed/NCBI
3	Vykhovanets EV, Resnick MI, MacLennan GT and Gupta S: Experimental rodent models of prostatitis: Limitations and potential. Prostate Cancer Prostatic Dis. 10:15–29. 2007. View Article : Google Scholar : PubMed/NCBI
4	Krieger JN, Nyberg L Jr and Nickel JC: NIH consensus definition and classification of prostatitis. JAMA. 282:236–237. 1999. View Article : Google Scholar : PubMed/NCBI
5	McNaughton Collins M, MacDonald R and Wilt TJ: Diagnosis and treatment of chronic abacterial prostatitis: A systematic review. Ann Intern Med. 133:367–381. 2000. View Article : Google Scholar : PubMed/NCBI
6	Hao ZY, Li HJ, Wang ZP, Xing JP, Hu WL, Zhang TF, Zhang XS, Zhou J, Tai S and Liang CZ: The prevalence of erectile dysfunction and its relation to chronic prostatitis in Chinese men. J Androl. 32:496–501. 2011. View Article : Google Scholar : PubMed/NCBI
7	Delongchamps NB, de la Roza G, Chandan V, Jones R, Sunheimer R, Threatte G, Jumbelic M and Haas GP: Evaluation of prostatitis in autopsied prostates-is chronic inflammation more associated with benign prostatic hyperplasia or cancer? J Urol. 179:1736–1740. 2008. View Article : Google Scholar : PubMed/NCBI
8	Sfanos KS and De Marzo AM: Prostate cancer and inflammation: The evidence. Histopathology. 60:199–215. 2012. View Article : Google Scholar : PubMed/NCBI
9	Schroder K and Tschopp J: The inflammasomes. Cell. 140:821–832. 2010. View Article : Google Scholar : PubMed/NCBI
10	Jo EK, Kim JK, Shin DM and Sasakawa C: Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 13:148–159. 2016. View Article : Google Scholar : PubMed/NCBI
11	Strowig T, Henao-Mejia J, Elinav E and Flavell R: Inflammasomes in health and disease. Nature. 481:278–286. 2012. View Article : Google Scholar : PubMed/NCBI
12	Deretic V: Autophagy in infection. Curr Opin Cell Biol. 22:252–262. 2010. View Article : Google Scholar : PubMed/NCBI
13	He C and Klionsky DJ: Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 43:67–93. 2009. View Article : Google Scholar : PubMed/NCBI
14	Kroemer G, Mariño G and Levine B: Autophagy and the integrated stress response. Mol Cell. 40:280–293. 2010. View Article : Google Scholar : PubMed/NCBI
15	Harris J, Hartman M, Roche C, Zeng SG, O'Shea A, Sharp FA, Lambe EM, Creagh EM, Golenbock DT, Tschopp J, et al: Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem. 286:9587–9597. 2011. View Article : Google Scholar : PubMed/NCBI
16	Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, et al: Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 456:264–268. 2008. View Article : Google Scholar : PubMed/NCBI
17	Su Y, Lu J, Chen X, Liang C, Luo P, Qin C and Zhang J: Rapamycin alleviates hormone imbalance-induced chronic nonbacterial inflammation in rat prostate through activating autophagy via the mTOR/ULK1/ATG13 signaling pathway. Inflammation. 41:1384–1395. 2018. View Article : Google Scholar : PubMed/NCBI
18	Liu RF, Fu G, Li J, Yang YF, Wang XG, Bai PD and Chen YD: Roles of autophagy in androgen-induced benign prostatic hyperplasia in castrated rats. Exp Ther Med. 15:2703–2710. 2018.PubMed/NCBI
19	Meng Y, Pan M, Zheng B, Chen Y, Li W, Yang Q, Zheng Z, Sun N, Zhang Y and Li X: Autophagy attenuates angiotensin ii-induced pulmonary fibrosis by inhibiting redox imbalance-mediated NOD-like receptor family pyrin domain containing 3 inflammasome activation. Antioxid Redox Signal. May 7–2018;(Epub ahead of print).
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS, Baba M, Baehrecke EH, Bahr BA, Ballabio A, et al: Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 4:151–175. 2008. View Article : Google Scholar : PubMed/NCBI
22	Liu KJ, Chatta GS, Twardzik DR, Vedvick TS, True LD, Spies AG and Cheever MA: Identification of rat prostatic steroid-binding protein as a target antigen of experimental autoimmune prostatitis: Implications for prostate cancer therapy. J Immunol. 159:472–480. 1997.PubMed/NCBI
23	Kaplan L, Lee C and Schaeffer AJ: Effect of castration on experimental bacterial prostatitis in rats. Prostate. 4:625–630. 1983. View Article : Google Scholar : PubMed/NCBI
24	Naslund MJ, Strandberg JD and Coffey DS: The role of androgens and estrogens in the pathogenesis of experimental nonbacterial prostatitis. J Urol. 140:1049–1053. 1988. View Article : Google Scholar : PubMed/NCBI
25	Robinette CL: Sex-hormone-induced inflammation and fibromuscular proliferation in the rat lateral prostate. Prostate. 12:271–286. 1988. View Article : Google Scholar : PubMed/NCBI
26	Bernoulli J, Yatkin E, Konkol Y, Talvitie EM, Santti R and Streng T: Prostatic inflammation and obstructive voiding in the adult Noble rat: Impact of the testosterone to estradiol ratio in serum. Prostate. 68:1296–1306. 2008. View Article : Google Scholar : PubMed/NCBI
27	Kamijo T, Sato S and Kitamura T: Effect of cernitin pollen-extract on experimental nonbacterial prostatitis in rats. Prostate. 49:122–131. 2001. View Article : Google Scholar : PubMed/NCBI
28	Keith IM, Jin J, Neal D Jr, Teunissen BD and Moon TD: Cell relationship in a Wistar rat model of spontaneous prostatitis. J Urol. 166:323–328. 2001. View Article : Google Scholar : PubMed/NCBI
29	Jia YL, Liu X, Yan JY, Chong LM, Li L, Ma AC, Zhou L and Sun ZY: The alteration of inflammatory markers and apoptosis on chronic prostatitis induced by estrogen and androgen. Int Urol Nephrol. 47:39–46. 2015. View Article : Google Scholar : PubMed/NCBI
30	Ozaki E, Campbell M and Doyle SL: Targeting the NLRP3 inflammasome in chronic inflammatory diseases: Current perspectives. J Inflamm Res. 8:15–27. 2015.PubMed/NCBI
31	Jiang H, He H, Chen Y, Huang W, Cheng J, Ye J, Wang A, Tao J, Wang C, Liu Q, et al: Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med. 214:3219–3238. 2017. View Article : Google Scholar : PubMed/NCBI
32	Broz P and Monack DM: Molecular mechanisms of inflammasome activation during microbial infections. Immunol Rev. 243:174–190. 2011. View Article : Google Scholar : PubMed/NCBI
33	Vincent JA and Mohr S: Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes. 56:224–230. 2007. View Article : Google Scholar : PubMed/NCBI
34	Park MC, Park YB and Lee SK: Elevated interleukin-18 levels correlated with disease activity in systemic lupus erythematosus. Clin Rheumatol. 23:225–229. 2004. View Article : Google Scholar : PubMed/NCBI
35	Kanneganti TD: Inflammatory bowel disease and the NLRP3 inflammasome. N Engl J Med. 377:694–696. 2017. View Article : Google Scholar : PubMed/NCBI
36	Basiorka AA, McGraw KL, Abbas-Aghababazadeh F, McLemore AF, Vincelette ND, Ward GA, Eksioglu EA, Sallman DA, Ali NA, Padron E, et al: Assessment of ASC specks as a putative biomarker of pyroptosis in myelodysplastic syndromes: An observational cohort study. Lancet Haematol. 5:e393–e402. 2018. View Article : Google Scholar : PubMed/NCBI
37	Wirawan E, Lippens S, Vanden Berghe T, Romagnoli A, Fimia GM, Piacentini M and Vandenabeele P: Beclin1: A role in membrane dynamics and beyond. Autophagy. 8:6–17. 2012. View Article : Google Scholar : PubMed/NCBI
38	Levine B and Kroemer G: Autophagy in the pathogenesis of disease. Cell. 132:27–42. 2008. View Article : Google Scholar : PubMed/NCBI
39	Mizushima N, Levine B, Cuervo AM and Klionsky DJ: Autophagy fights disease through cellular self-digestion. Nature. 451:1069–1075. 2008. View Article : Google Scholar : PubMed/NCBI
40	Nakatogawa H, Suzuki K, Kamada Y and Ohsumi Y: Dynamics and diversity in autophagy mechanisms: Lessons from yeast. Nat Rev Mol Cell Biol. 10:458–467. 2009. View Article : Google Scholar : PubMed/NCBI
41	Mizushima N and Yoshimori T: How to interpret LC3 immunoblotting. Autophagy. 3:542–545. 2007. View Article : Google Scholar : PubMed/NCBI
42	Barth S, Glick D and Macleod KF: Autophagy: Assays and artifacts. J Pathol. 221:117–124. 2010. View Article : Google Scholar : PubMed/NCBI
43	Kroemer G: Autophagy: A druggable process that is deregulated in aging and human disease. J Clin Invest. 125:1–4. 2015. View Article : Google Scholar : PubMed/NCBI
44	Nilsson P and Saido TC: Dual roles for autophagy: Degradation and secretion of Alzheimer's disease Aβ peptide. Bioessays. 36:570–578. 2014. View Article : Google Scholar : PubMed/NCBI
45	Ehrnhoefer DE, Martin DDO, Schmidt ME, Qiu X, Ladha S, Caron NS, Skotte NH, Nguyen YTN, Vaid K, Southwell AL, et al: Preventing mutant huntingtin proteolysis and intermittent fasting promote autophagy in models of Huntington disease. Acta Neuropathol Commun. 6:162018. View Article : Google Scholar : PubMed/NCBI
46	Choi S, Shin H, Song H and Lim HJ: Suppression of autophagic activation in the mouse uterus by estrogen and progesterone. J Endocrinol. 221:39–50. 2014. View Article : Google Scholar : PubMed/NCBI
47	Wang F, Xiao J, Shen Y, Yao F and Chen Y: Estrogen protects cardiomyocytes against lipopolysaccharide by inhibiting autophagy. Mol Med Rep. 10:1509–1512. 2014. View Article : Google Scholar : PubMed/NCBI
48	Fu J, Hao L, Tian Y, Liu Y, Gu Y and Wu J: miR-199a-3p is involved in estrogen-mediated autophagy through the IGF-1/mTOR pathway in osteocyte-like MLO-Y4 cells. J Cell Physiol. 233:2292–2303. 2018. View Article : Google Scholar : PubMed/NCBI
49	Harris J, Lang T, Thomas JPW, Sukkar MB, Nabar NR and Kehrl JH: Autophagy and inflammasomes. Mol Immunol. 86:10–15. 2017. View Article : Google Scholar : PubMed/NCBI
50	Zhou W, Liu X, Cheng K, Zhang X, Lu J and Hu R: X-11-5-27, a daidzein derivative, inhibits NLRP3 inflammasome activity via promoting autophagy. Exp Cell Res. 360:320–327. 2017. View Article : Google Scholar : PubMed/NCBI
51	Song Y, Xue H, Liu TT, Liu JM and Chen D: Rapamycin plays a neuroprotective effect after spinal cord injury via anti-inflammatory effects. J Biochem Mol Toxicol. 29:29–34. 2015. View Article : Google Scholar : PubMed/NCBI