Osteoprotegerin production by human intestinal epithelial cells: a potential regulator of mucosal immune responses

Abstract

Receptor activator of NF-κB (RANK) and its ligand (RANKL) are important members of the TNF receptor (TNFR) and TNF superfamilies, respectively. RANK is expressed on osteoclasts, T-lymphocytes, and dendritic cells, and its ligation with RANKL leads to cellular activation. However, another member of the TNFR family, osteoprotegerin (OPG), acts as a decoy receptor, binding to RANKL and preventing its interaction with RANK. Furthermore, OPG also binds TNF-related apoptosis-inducing ligand (TRAIL), an important regulator of cell survival. OPG is therefore an important regulator of bone metabolism and immune responses. Although intestinal epithelial cells (IEC) express some members of the TNF/TNFR superfamilies, the roles of OPG and RANKL in the intestinal mucosa has not been investigated. Here, we report that various human IEC lines constitutively express OPG mRNA and protein as well as mRNA for RANKL. Furthermore, human colonic epithelium constitutively expressed OPG, and this expression was increased in inflamed tissue. All of the IEC lines tested released OPG into the culture supernatant under standard culture conditions. Whereas TNF-α increased OPG protein secretion by HT29 cells, the cytokines IL-1β and IFN-γ had little, if any, effect. Furthermore, the culture supernatant from untreated HT29 cells abrogated TRAIL-induced inhibition of Jurkat T-cell proliferation and inhibited osteoclast activity in an in vitro model of bone resorption. Taken together, our data indicate that OPG is constitutively produced by IEC, could be upregulated by TNF-α, and is biologically active. Thus IEC-derived OPG may represent an important mucosal immunoregulatory factor and may be involved in bone physiology.

Human Primary Intestinal Epithelial Cells as an Improved In Vitro Model for Cryptosporidium parvum Infection

“…Previous studies have shown the utility of antiapoptotic molecules to extend the life of intestinal primary cells after detaching them from the intestinal tissue (14,23). Thus, here we added recombinant osteoprotegerin (OPG) during the transport of the tissue and immediately after PEC isolation to prevent anoikis, OPG is a tumor necrosis factor alpha receptor family member, which acts as a decoy by binding TRAIL and TRANCE, blunting the apoptosis pathway (24)(25)(26). We previously demonstrated that intestinal epithelial cells produce OPG in response to Cryptosporidium infection (25).…”

Antianoikis Effect of Nuclear Factor-κB through Up-regulated Expression of Osteoprotegerin, BCL-2, and IAP-1

“…Some prior studies have indicated an antiapoptotic function for OPG wherein OPG acts as a decoy receptor for TNF-related apoptosis-inducing ligand (TRAIL), which in cancer cells induces a death receptor pathway of apoptosis through the DR5 receptor (56,57). The functional antianoikis effect of OPG that was shown by restoration of OPG expression in NF-B-inactive cells suggests that TRAIL might be involved in the induction of anoikis.…”

Immunology of breast milk

“…35 It can bind to TNF-related apoptosis-inducing ligand (TRAIL) and induce caspase-dependent apoptosis, especially in Th1 cells, which is supposed to be important to regulate the balance of Th1/Th2 in the development of the immune system in newborns. 36 Soluble CD14 (sCD14) Colostrum and breast milk contain high levels of the sCD14 molecule, exceeding the concentration found in the serum more than 20 times. 37 This component affects the modulation of innate and adaptive immune responses in the intestine during bacterial colonization and thus controls homeostasis in the newborn's intestine.…”