The interplay of BMP4 and IL-7 regulates the apoptosis of intestinal intraepithelial lymphocytes under conditions of ischemia/reperfusion

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.