Enteric glia modulate epithelial cell proliferation and differentiation through 15-deoxy-12,14-prostaglandin J2.

INSERM U913 and Institut des Maladies de l'Appareil Digestif, 1, place Alexis Ricordeau, 44093 Nantes Cedex 01, France.
The Journal of Physiology (Impact Factor: 4.38). 07/2010; 588(Pt 14):2533-44. DOI: 10.1113/jphysiol.2010.188409
Source: PubMed

ABSTRACT The enteric nervous system (ENS) and its major component, enteric glial cells (EGCs), have recently been identified as a major regulator of intestinal epithelial barrier functions. Indeed, EGCs inhibit intestinal epithelial cell (IEC) proliferation and increase barrier resistance and IEC adhesion via the release of EGC-derived soluble factors. Interestingly, EGC regulation of intestinal epithelial barrier functions is reminiscent of previously reported peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent functional effects. In this context, the present study aimed at identifying whether EGC could synthesize and release the main PPARgamma ligand, 15-deoxy-(12,14)-prostaglandin J2 (15dPGJ2), and regulate IEC functions such as proliferation and differentiation via a PPARgamma dependent pathway. First, we demonstrated that the lipocalin but not the haematopoetic form for prostaglandin D synthase (PGDS), the enzyme responsible of 15dPGJ2 synthesis, was expressed in EGCs of the human submucosal plexus and of the subepithelium, as well as in rat primary culture of ENS and EGC lines. Next, 15dPGJ2 was identified in EGC supernatants of various EGC lines. 15dPGJ2 reproduced EGC inhibitory effects upon IEC proliferation, and inhibition of lipocalin PGDS expression by shRNA abrogated these effects. Furthermore, EGCs induced nuclear translocation of PPARgamma in IEC, and both EGC and 15dPGJ2 effects upon IEC proliferation were prevented by the PPARgamma antagonist GW9662. Finally, EGC induced differentiation-related gene expression in IEC through a PPARgamma-dependent pathway. Our results identified 15dPGJ2 as a novel glial-derived mediator involved in the control of IEC proliferation/differentiation through activation of PPARgamma. They also suggest that alterations of glial PGDS expression may modify intestinal epithelial barrier functions and be involved in the development of pathologies such as cancer or inflammatory bowel diseases.

  • [Show abstract] [Hide abstract]
    ABSTRACT: As the major constituent of Radix Astragali, Astragalus polysaccharide (APS) is known for its anti-inflammation and immunomodulatory functions. The objective of this study was to investigate the effect of APS on inflammatory response and structural changes in lipopolysaccharide (LPS)-infected Caco2 cells. Caco2 cells were co-cultured with APS and LPS, with APS added after the addition of LPS (post-addition), before the addition of LPS (pre-addition), or simultaneously with the addition of LPS (simultaneous addition). The mRNA expression of inflammatory indicators and tight junctions was measured by RT-qPCR. Short circuit current (Isc) was recorded by an Ussing chamber system. Addition of APS significantly down-regulated the expression of TNF-α, IL-1β and IL-8 (P<0.05) and the Isc levels (P<0.05) of LPS-infected Caco2 cells for all three administration treatments. The minimum anti-inflammatory concentration of APS was 50, 100, and 100μg/mL for pre-, post-, and simultaneous additions of APS, respectively. The mRNA expression of zonula occludens-1 (ZO-1) and occludin was significantly up-regulated for post- and pre-additions of APS, respectively (P<0.05). Results suggested that APS had anti-inflammatory and structure protective properties for LPS-infected Caco2 cells, and may be used as a preventative treatment for intestine cells.
    International journal of biological macromolecules 08/2013; · 2.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study evaluates the effect of sulfated Astragalus polysaccharide (SAPS) on inflammatory reaction induced by LPS in Caco2 cells. Sulfated modification was conducted using the chlorosulfonic acid-pyridine method. Caco2 cells were cultured with 25, 50 and 100μg/mL SAPS or 100μg/mL Astragalus polysaccharide (APS) for 24h. Then, 1μg/mL LPS was added for the next 24h to trigger an inflammatory response. DMEM culture medium was used as a blank control. In present study, LPS stimulation significantly increased the mRNA expression of TNF-α, IL-1β, IL-8 and TLR4, and reduced the expression of ZO-1 and occludin. Compared with the LPS control group, APS (100μg/mL) or SAPS (100μg/mL) administration decreased the expression of TNF-α, IL-1β and IL-8. Moreover, 25μg/mL and 50μg/mL SAPS down-regulated TNF-α and IL-1β expression. APS administration (100μg/mL) up-regulated occludin expression, but did not affect ZO-1 expression. However, the expression of ZO-1 and occludin was up-regulated by lower dose SAPS administration (25μg/mL and 50μg/mL). Compared with the other groups, the expression of TLR4 was lower in the SAPS group at all concentrations of SAPS. These results suggest that SAPS was to be a more effective anti-inflammatory agent than APS in vitro.
    International journal of biological macromolecules 06/2013; · 2.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acute intestinal ischemia reperfusion (IR) injury is often associated with intestinal epithelial barrier (IEB) dysfunction. Enteric glial cells (EGCs) play an essential role in maintaining the integrity of IEB functions. However, the precise mechanism of EGCs under IR stimulation remains unclear. Here, we report that EGCs are closely involved in the modulation of IEB functions in response to IR challenge. The intestinal IR treatment led to the significant upregulation of the EGC activation marker, glial fibrillary acidic protein, accompanied by the increasing abundance of glial-derived neurotrophic factor (GDNF) and inducible nitric oxidase (iNOS) proteins, which was also confirmed in in vitro hypoxia reoxygenation (HR) tests. Co-culturing with EGCs attenuated the tight junctional abnormalities, blocked the downregulation of ZO-1 and occludin protein expression, and relieved the decrease of permeability of intestinal epithelial cell (IEC) monolayers under HR treatment. Furthermore, exogenous GDNF administration displays the barrier-protective effects similar to EGCs against HR stimulation, while RNA interference-mediated knockdown of GDNF significantly inhibited the protective capability of EGCs. The expression of both GDNF and iNOS proteins of EGCs was significantly upregulated by co-culturing with IECs, which was further increased by HR treatment. Interestingly, through inhibiting iNOS activity, the barrier-protective effect of EGCs was influenced in normal condition but enhanced in HR condition. These results suggest that GDNF plays an important role in the barrier-protective mechanism of activated EGCs under IR stimulation, whereas EGCs (via iNOS release) are also involved in intestinal inflammation response, which may contribute to IEB damage induced by IR injury.
    Molecular neurobiology. 05/2014;

Full-text (2 Sources)

Available from
May 21, 2014