Role of suppressor of cytokine signalling 3 in regulating microbe‐mediated intestinal epithelial proliferation and repair

Abstract

The gut is lined with a single layer of intestinal epithelial cells (IEC) that functions as a barrier between a plethora of luminal antigens, including commensal bacteria, and a primed immune system. In a healthy adult, the entire epithelium is replaced about every 5 days; therefore maintenance of the IEC barrier is essential in maintaining mucosal homeostasis. IEC express Toll-like receptors (TLR) which recognise microbial ligands and recent evidence proposes that IEC homeostasis and repair are mediated through TLR-induced inflammatory pathways. Resistance to helminthic infection relies on hyperproliferation of IEC to eliminate the parasites. Suppressor of cytokine signalling 3 (SOCS3) is a natural endogenous modulator of epithelial turnover which limits hyperproliferation of aberrant IEC predisposing to dysplasia and cancer. We have used model human SW480 and Caco2 IEC cell lines to study IEC proliferation and wound healing responses to lipopolysaccharide (LPS; 1μg/ml)and Trichuris muris secreted protein (ES; 5 μg/ml); to determine their effects on epithelial proliferation and repair and define the role of SOCS3 in modulating microbe-mediated IEC homeostasis. Exposure to LPS and ES significantly enhanced SW480 proliferation compared with no treatment controls after 48h culture by 12 ± 1.6% and 21 ± 6.5% respectively. Increased wound healing in differentiated Caco2 monolayers was observed at 6h following treatment with LPS and ES, but this increased was not observed at 24, 48 or 72h compared with no treatment controls. IEC over-expression of SOCS3 inhibited microbe-induced increases in proliferation (LPS 17 ± 4%; ES 13 ± 3.5%), but did not significantly change wound healing responses. These findings suggest that although SOCS3 may limit microbe-induced proliferation of IEC, SOCS3 does not inhibit initial epithelial wound healing responses.