TLR signaling at the intestinal epithelial interface

Abstract

The intestinal epithelium provides a critical interface between lumenal bacteria and the mucosal immune system. Whereas normal commensal flora do not trigger acute inflammation, pathogenic bacteria trigger a potent inflammatory response. Our studies emanate from the hypothesis that the intestinal epithelium is normally hyporesponsive to commensal pathogen-associated molecular patterns (PAMPs) such as LPS. Our data demonstrate that normal human colonic epithelial cells and lamina propria cells express low levels of TLR4 and its co-receptor MD-2. This expression pattern is mirrored by intestinal epithelial cell (IEC) lines. Co-expression of TLR4 and MD-2 is necessary and sufficient for LPS responsiveness in IEC. Moreover, LPS sensing occurs along the basolateral membrane of polarized IEC in culture. Expression of MD-2 is regulated by IFN-gamma. Cloning of the MD-2 promoter demonstrates that promoter activity is increased by IFN-gamma and blocked by the STAT inhibitor SOCS3. We conclude from our studies that the intestinal epithelium down-regulates expression of TLR4 and MD-2 and is LPS unresponsive. The Th1 cytokine IFN-gamma up-regulates expression of MD-2 in a STAT-dependent fashion. The results of our studies have important implications for understanding human inflammatory bowel diseases.

Cutting Edge: FimH Adhesin of Type 1 Fimbriae Is a Novel TLR4 Ligand

“…Thus, it is not surprising that mucosal epithelial cells express TLR4 but not CD14, a coreceptor required for LPS recognition (19). As such, FimH serves as a potent stimulator of the innate immune response via interaction with TLR4 independently of LPS, allowing for recognition of pathogenic E. coli.…”

Neutrophil transepithelial migration: role of toll-like receptors in mucosal inflammation

“…However, recent studies have demonstrated that TLR4 and MD-2 are expressed by a number of epithelial cells, but at low levels (Abreu et al 2002, Backhed & Hornef 2003. Furthermore, co-transfection of intestinal epithelial cells with TLR4 and MD-2 enhanced LPS responsiveness, thus suggesting that low expression levels of TLR4 and MD-2 may explain epithelial hyporesponsiveness to lumenal LPS (Abreu et al 2002(Abreu et al , 2003. However, it has been reported that TLR2 and TLR4 expression is up-regulated under inflammatory conditions (Abreu et al 2002, Hausmann et al 2002, which could provide a mechanism for certain inflammatory diseases of the intestine.…”

“…Given the important role of the epithelial tight junction, it is easy to envision how disruption of the epithelial barrier or how translocation of bacterial products across the epithelium could result in activation of TLRs. Indeed, despite the presence of 10 14 bacteria per gram of tissue in the colon (Abreu et al 2003) that produce high levels of immunoreactive LPS (Lorenz et al 2002), the mucosal immune system remains remarkably at a basal physiological state. The fact that epithelial tissues do not express apical GPI-linked CD14 may explain the absence of an inflammatory response to the normal flora (Fenton & Golenbock 1998, Viriyakosol et al 2000.…”

TLRs Regulate the Gatekeeping Functions of the Intestinal Follicle-Associated Epithelium

“…Epithelial cells on intestinal villi act as sensors of the luminal environment, and intestinal epithelial cell monolayers in vitro can release inflammatory cytokines in response to pathogen attachment and invasion (1,2). Intestinal epithelial cells express a variety of potential sensing receptors, including TLRs (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), that may play a role in mucosal responses to microbial components.…”