LPS/TLR4 Signaling Enhances TGF-β Response Through Downregulating BAMBI During Prostatic Hyperplasia

Abstract

Compelling evidence suggests that benign prostatic hyperplasia (BPH) development involves accumulation of mesenchymal-like cells derived from the prostatic epithelium by epithelial-mesenchymal transition (EMT). Transforming growth factor (TGF)-β induces EMT phenotypes with low E-cadherin and high vimentin expression in prostatic epithelial cells. Here we report that LPS/TLR4 signalling induces down-regulation of the bone morphogenic protein and activin membrane-bound inhibitor (BAMBI), which enhances TGF-β signalling in the EMT process during prostatic hyperplasia. Additionally, we found that the mean TLR4 staining score was significantly higher in BPH tissues with inflammation compared with BPH tissues without inflammation (5.13 ± 1.21 and 2.96 ± 0.73, respectively; P < 0.001). Moreover, patients with inflammatory infiltrate were more likely to have a higher age (P = 0.020), BMI (P = 0.026), prostate volume (P = 0.024), total IPSS score (P = 0.009) and IPSS-S (P < 0.001). Pearson’s correlation coefficient and multiple regression analyses demonstrated that TLR4 mRNA expression level was significantly positively associated with age, BMI, serum PSA levels, urgency and nocturia subscores of IPSS in the inflammatory group. These findings provide new insights into the TLR4-amplified EMT process and the association between TLR4 levels and storage LUTS, suggesting chronic inflammation as vital to the pathogenesis of BPH.

BAMBI is a novel HIF1-dependent modulator of TGFβ-mediated disruption of cell polarity during hypoxia

“…However, it lacks the cytoplasmic kinase domain and is therefore generally thought to function as a negative regulator of both TGFβ and BMP signaling (Guillot et al, 2012;Tsang et al, 2000). In line with this, depletion of BAMBI expression reportedly enhances the TGFβ signaling response in cancer cell lines (He et al, 2016;Marwitz et al, 2016). Contrary data have also been reported, however, as high levels of BAMBI expression have been correlated with increased plasma TGF-β1 levels in chronic obstructive pulmonary disease patients (Zhang et al, 2016).…”

Integrin αvβ6 mediates epithelial-mesenchymal transition in human bronchial epithelial cells induced by lipopolysaccharides of Pseudomonas aeruginosa via TGF-β1-Smad2/3 signaling pathway

“…It is noteworthy that toll-like receptor 4 (TLR4), a receptor for LPS which could enhance TGF-β signaling pathway, has been reported to play a key role in the process of organ fibrogenesis and LPS-induced EMT process (Guillot et al 2004;Seki et al 2007;He et al 2016;Tang et al 2018;Vidya et al 2018). And interestingly, previous studies implicated that cross talks exist between toll-like receptors and integrin αvβ6 (Pittet et al 2013;Jolly et al 2014), so integrin αvβ6 might be a therapeutic target for toll-like receptor-mediated fibrogenesis process.…”

Aberrant Transforming Growth Factor-β Activation Recruits Mesenchymal Stem Cells During Prostatic Hyperplasia

“…The critical role of TGF‐β in prostatic stromal accumulation, which eventually leads to BPH, is well known , , . Aberrant activation of TGF‐β canonical signaling has been observed in both rodent and human prostatic hyperplasia , . Recent studies showed that the murine pan‐specific TGF‐β neutralizing monoclonal antibody, 1D11, had the effect of pharmacological inhibition of TGF‐β in different mouse models, including osteogenesis imperfecta , chronic nephropathy , and asthma .…”

“…High levels of transforming growth factor‐β (TGF‐β) activities are often observed in the pathogenesis of BPH . Induction of fibroplasia and collagenous micronodules was observed with TGF‐β1 overexpression in transgenic mice .…”