| beta-arrestins are dynamic multifaceted proteins that play roles in a variety of cellular functions from receptor internalization and desensitization to second-messenger signaling and regulation. Although beta-arrestins are ubiquitously expressed throughout the body, their expression level in different cells lines is not the same. It is this difference in gene and protein expression that maybe the underlying factor in platelet-activating factor mediated cell survival or cell death. Platelet-activating factor (PAF) is a pro-inflammatory mediator that has been implicated in the pathogenesis of multiple gastrointestinal disorders, including inflammatory bowel disease and neonatal necrotizing enterocolitis (NEC). NEC is of particular importance because it is a major cause of mortality and morbidity of premature infants born weighing less than 1500 grams at birth. PAF has been implicated in the onset and progression of NEC, and beta-arrestins are known to interact with PAF's cognate receptor, platelet-activating factor receptor (PTAFR). Thus we wanted to find out if beta-arrestin expression and function had any influence on NEC. In a modified rodent model of NEC, using seven-day old mice, we found that the inflammatory response was accompanied by an increased rate of proliferation of crypt stem cells. In mice where the PAF receptor (PTAFR) gene was disrupted (PTAFR KO), both the inflammatory response and the increase of stem cell proliferation were absent. beta-arrestin mRNA and protein exhibited a site and isoform-specific expression pattern along the crypt/villus axis. In both mice and rats, high beta-arrestin2 (ARRB2) expression was exclusive to the crypt epithelium, but high beta-arrestin1 (ARRB1) expression was found in the villus epithelium. In IEC-6, rat small intestinal epithelial cells that exhibit high ARRB1 and almost absent ARRB2 expression, PAF induces apoptosis, an effect which is antagonized by heterologous overexpression of ARRB2, or shRNA-mediated knock-down of ARRB1. Formula feeding (FF), which sensitizes rat pups to hypoxia-induced epithelial apoptosis, produced altered arrestin isoform expression in neonatal rats. The result was increased ARRB1 expression in this group. These findings support the notion that asymmetrical beta-arrestin isoform expression along the crypt/villus epithelial developmental axis plays a potentially significant role in regulating inflammation-related cell fate decisions. |
