The c-Jun N-terminal kinase (JNK) pathway is activated in human interstitial cystitis (IC) and rat protamine sulfate induced cystitis - PubMed (original) (raw)

The c-Jun N-terminal kinase (JNK) pathway is activated in human interstitial cystitis (IC) and rat protamine sulfate induced cystitis

Jiang Zhao et al. Sci Rep. 2016.

Abstract

The pathogenesis of bladder pain syndrome/interstitial cystitis (BPS/IC) is currently unclear. However, inflammation has been suggested to play an important role in BPS/IC. JNK downstream signaling plays an important role in numerous chronic inflammatory diseases. However, studies of the JNK pathway in BPS/IC are limited. In this study, we investigated the role of the JNK pathway in human BPS/IC and rat protamine sulfate (PS)-induced cystitis and examined the effect of the selective JNK inhibitor SP600125 on rat bladder cystitis. In our study, we demonstrated that the JNK signaling pathway was activated (the expression of JNK, c-Jun, p-JNK, p-c-Jun, IL-6 and TNF-α were significantly increasing in BPS/IC compared to the non-BPS/IC patients) and resulted in inflammation in human BPS/IC. Further animal models showed that the JNK pathway played an important role in the pathogenesis of cystitis. JNK inhibitors, SP600125, effectively inhibited the expression of p-JNK, p-c-Jun, IL-6 and TNF-α. The inhibition of these pathways had a protective effect on PS-induced rat cystitis by significantly decreasing histological score and mast cell count and improving bladder micturition function (micturition frequency significantly decreasing and bladder capacity significantly increasing). Therefore, JNK inhibition could be used as a potential treatment for BPS/IC.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1

Figure 1. Histological evaluation in human BPS/IC.

(A,B) Representative HE and toluidine blue staining (x20) photomicrograph images of numerous inflammatory cells and mast cell infiltration into the bladder muscular layer, arrows demonstrate inflammatory cells and mast cell. (C) The chart indicates the number of mast cells in muscular layer in control (n = 7) and BPS/IC humans (n = 6). The data are expressed as the mean ± SD, *P < 0.05, BPS/IC vs. control.

Figure 2

Figure 2. Histological evaluation in rat PS-induced cystitis.

(A,B) Representative HE and toluidine blue staining (x20) photomicrograph images of pathologic changes and mast cell infiltration into the bladder muscular layer in PS-treated rats, arrows demonstrate mast cell.

Figure 3

Figure 3. The expression of JNK, c-Jun, p-JNK, p-c-Jun, IL-6 and TNF-α changes in human BPS/IC using Western blot.

(A) Typical protein bands showing the increased expression of JNK, c-Jun, p-JNK, p-c-Jun, IL-6 and TNF-α in BPS/IC bladder. (B–D) The chart shows the expression of JNK, c-Jun, p-JNK, p-c-Jun, IL-6 and TNF-α in control (n = 8) and BPS/IC humans (n = 9). The data are expressed as the mean ± SD, *P < 0.05, BPS/IC vs. control.

Figure 4

Figure 4. The expression and location of p-JNK changes in human BPS/IC using immunohistochemistry.

(A) Representative immunohistochemistry (x20) shows p-JNK expression in the bladder muscles layers of mesenchymal cells (including inflammatory cells) and detrusor myocytes, arrows demonstrate the p-JNK expression. (B) The chart indicates the expression change of p-JNK in control (n = 7) and BPS/IC humans (n = 6). The data are expressed as the mean ± SD, *P < 0.05, BPS/IC vs. control.

Figure 5

Figure 5. Evaluation of JNK, c-Jun, p-JNK, p-c-Jun, IL-6 and TNF-α changes in rat PS-induced cystitis using Western blot.

(A) Typical protein bands showing increased expression of JNK, c-Jun p-JNK, p-c-Jun, IL-6 and TNF-α in PS-treated rats. (B–D) The chart shows the expression of JNK, c-Jun, p-JNK, p-c-Jun, IL-6 and TNF-α in PS-treated rats (N = 8). The data are expressed as the mean ± SD, *P < 0.05, NS, PS, PPCES + PS and SP600125 + PS vs. control, ▲P < 0.05, SP600125 + PS vs. PS and PPCES + PS, #P < 0.05, SP600125 + PS vs. PS.

Figure 6

Figure 6. Representative cystometric traces of control, NS, PS, PPCES + PS and SP600125 + PS groups.

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