The interplay of BMP4 and IL‑7 regulates the apoptosis of intestinal intraepithelial lymphocytes under conditions of ischemia̸reperfusion.

Abstract

The number and function of intestinal intraepithelial lymphocytes (IELs) have been found to be significantly reduced following induction of acute intestinal mucosal damage via intestinal ischemia/reperfusion (I/R). However, the mechanism underlying this reduction remains unclear. Therefore, it was hypothesized that the interplay of bone morphogenetic protein (BMP)4 and interleukin (IL)-7 regulates IEL function and number. Recent studies have demonstrated that the different components of the BMP2/4 signaling pathway are expressed in intestinal epithelial cells (IECs) via the activation of nuclear factor (NF)-κB. In the present study, reverse transcription-polymerase chain reaction analysis and flow cytometry demonstrated that IELs express BMP receptors (BMPRIA, BMPRIB, ActRIA and BMPRII) and non-canonical signal transduction molecules (NF-κB). An in vivo mouse intestinal I/R model was used, and I/R was shown to increase the expression of BMP4 in IECs and upregulate the expression levels of BMPRIA, BMPRIB and phosphorylated NF-κB in IELs. Following isolation and culture of IELs, it was observed that exogenous BMP4 also upregulated the expression of BMPRIA and BMPRIB and activated NF-κB signaling in IELs, inducing IEL apoptosis. In addition, the rate of apoptosis of IELs decreased following treatment with the BMP-specific antagonist NOGGIN or with the NF-κB inhibitor pyrrolidine dithiocarbamate. Furthermore, it was observed that exogenous IL-7 can decrease BMP4 protein expression in IECs and the expression of phosphorylated NF-κB protein in IELs. The findings of the present study suggest that, under conditions of I/R, IEC-derived BMP4 activates NF-κB signaling in IELs, inducing IEL apoptosis, further aggravating the dysfunction of the intestinal mucosal barrier. However, these effects may be alleviated by IL-7 treatment. Therefore, BMP4 and IL-7 appear to be involved in the interaction between IECs and IELs and in the mechanism underlying intestinal mucosal barrier dysfunction.