Human colonic subepithelial myofibroblasts modulate transepithelial resistance and secretory response

Abstract

The epithelium of the gastrointestinal tract transports ions and water but excludes luminal microorganisms and toxic molecules. The factors regulating these important functions are not fully understood. Intestinal myofibroblasts lie subjacent to the basement membrane, at the basal surface of epithelial cells. We recently showed that primary cultures of adult human colonic subepithelial myofibroblasts express cyclooxygenase (COX)-1 and COX-2 enzymes and release bioactive transforming growth factor-β (TGF-β). In this study we have investigated the role of normal human colonic subepithelial myofibroblasts in the regulation of transepithelial resistance and secretory response in HCA-7 and T84 colonic epithelial cell lines. Cocultures of epithelial cells-myofibroblasts and medium conditioned by myofibroblasts enhanced transepithelial resistance and delayed mannitol flux. A panspecific antibody to TGF-β (but not piroxicam) antagonized this effect. In HCA-7 cells, myofibroblasts downregulated secretagogue-induced change in short-circuit current, and this effect was reversed by pretreatment of myofibroblasts with piroxicam. In contrast to HCA-7 cells, myofibroblasts upregulated the agonist-induced secretory response in T84 cells. This study shows that intestinal subepithelial myofibroblasts enhance barrier function and modulate electrogenic chloride secretion in epithelial cells. The enhancement of barrier function was mediated by TGF-β. In contrast, the modulation of agonist-induced change in short-circuit current was mediated by cyclooxygenase products. These findings suggest that colonic myofibroblasts regulate important functions of epithelial cells via distinct secretory products.

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

“…Incoming CD4 ϩ T cells differentiate primarily into Th1 effectors in the presence of IL-12p70 and IL-27. Th17 are also generated due to the presence of TGF␤, released primarily by colonic subepithelial myofibroblasts (68,69), and of IL-6 produced by LPDC and activated macrophages. However, following IL-12/ IL-27-induced Tbet expression in differentiating T cells, the Th17 phenotype is rapidly destabilized (55).…”

Characteristics of subepithelial fibroblasts as a mechano-sensor in the intestine: cell-shape-dependent ATP release and P2Y1 signaling

“…In addition to their direct sieve function, they may control the permeability of epithelium to ions, nutrients and water by releasing various cytokines, such as TGF-β, TNF-α, HGF, PGEs. These cytokines are secreted from subepithelial fibroblasts (Valentich et al, 1997;Plateroti et al, 1998) and modify the assembly of tight junctions of epithelium to change their permeability (Beltinger et al, 1999;Walsh et al, 2000). So, the subepithelial fibroblast network may work as a barrier or sieve by itself and by controlling the epithelium in the intestine.…”

Muscularis mucosae contraction evokes colonic secretion via prostaglandin synthesis and nerve stimulation

“…These cells lie adjacent to the mucosa, possess a variety of pharmacological receptors, and are a likely source of prostaglandin production in this region (4,36). This explanation is unlikely, given that histamine has minimal mucosal effects in the Ussing chamber when muscularis mucosae contractions are curtailed (28,30) but causes large TTX-and indomethacin-sensitive potential difference changes in the cylinder preparation where contractions are unimpeded.…”