The involvement of Pellino-1 downregulation in the modulation of visceral hypersensitivity via the TLR4/NF-κB pathway in the rat fastigial nucleus

Abstract

Irritable bowel syndrome (IBS) is a common functional bowel disorder whose key characteristics include chronic visceral hypersensitivity (CVH) and abnormal brain-gut interactions. Pellino-1 is an E3 ubiquitin ligase, mediating the degradation or modification of targeted proteins. Some brain regions, such as the fastigial nucleus (FN), may play important roles in CVH; however, the molecular mechanism underlying this phenomenon is not clear. In this study, we assessed the roles of Pellino-1 within the FN in modulating VH by generating a colorectal distention (CRD) model in male Sprague–Dawley rats. Our results showed that the downregulation of Pellino-1 in the fastigial nucleus (FN) was involved in the modulation of visceral hypersensitivity. The expression of Pellino-1 was downregulated in the FN of adult CRD rats compared with control rats, whereas TLR4 and NF-κB were upregulated in the CRD model. To overexpress Pellino-1, a lentivirus specifically expressing Pellino-1 and green fluorescent protein was administered into the FN. The overexpression of Pellino-1 increased the visceral sensitivity of CRD rats, and the expression of TLR4 and NF-κB increased further. After administration of TAK-242 (a specific TLR4 inhibitor), the visceral response to overexpression of Pellino-1 was reversed. Overall, the findings indicated the involvement of the FN in the development of CVH; the downregulation of Pellino-1 in the FN acted through the TLR4/NF-κB pathway to protect against CVH in a CRD rat model.