Candida albicansinfection leads to barrier breakdown and a MAPK/NF-κB mediated stress response in the intestinal epithelial cell line C2BBe1

Abstract

Intestinal epithelial cells (IEC) form a tight barrier to the gut lumen. Paracellular permeability of the intestinal barrier is regulated by tight junction proteins and can be modulated by microorganisms and other stimuli. The polymorphic fungus Candida albicans, a frequent commensal of the human mucosa, has the capacity of traversing this barrier and establishing systemic disease within the host. Infection of polarized C2BBe1 IEC with wild-type C. albicans led to a transient increase of transepithelial electric resistance (TEER) before subsequent barrier disruption, accompanied by a strong decline of junctional protein levels and substantial, but considerably delayed cytotoxicity. Time-resolved microarray-based transcriptome analysis of C. albicans challenged IEC revealed a prominent role of NF-κB and MAPK signalling pathways in the response to infection. Hence, we inferred a gene regulatory network based on differentially expressed NF-κB and MAPK pathway components and their predicted transcriptional targets. The network model predicted activation of GDF15 by NF-κB was experimentally validated. Furthermore, inhibition of NF-κB activation in C. albicans infected C2BBe1 cells led to enhanced cytotoxicity in the epithelial cells. Taken together our study identifies NF-κB activation as an important protective signalling pathway in the response of epithelial cells to C. albicans.

Pharmacological activation of ERβ by arctigenin maintains the integrity of intestinal epithelial barrier in inflammatory bowel diseases

“…As previously reported, the expression of TJ proteins can be regulated by multiple signaling pathways, including mitogen‐activated protein kinases (MAPKs), mammalian targets of rapamycin (mTOR), and myosin light chain kinase (MLCK). Figure A showed that arctigenin (3 µM) did not alter ERK, JNK, and P38 activation after stimulation with TNF‐α in Caco‐2 and HT‐29 cells, but inhibited the phosphorylation of mTOR and the downstream adaptor protein RPS6.…”

“…To shed light on the action mechanism of arctigenin, this work investigated its effects on the activation of three important pathways (MAPKs, mTOR, and MLCK) which are relevant in the expression of TJ proteins. [29][30][31] The results showed that arctigenin did not affect the activation of ERK, JNK and P38 induced by TNF-α in colon epithelial cells, but inhibited the phosphorylation of mTOR, the expression of MLCK and phosphorylation of MLC. When arctigenin was used in combination with rapamycin (an inhibitor of mTOR) or fasudil (an inhibitor of MLCK), rapamycin rather than fasudil augmented the promotion effect of arctigenin on the expression of occludin and ZO-1 in Caco-2 cells.…”

“…To date, the relationship between the activation of ERβ and the expression of TJ proteins and consequent barrier protection remains obscure, and multiple signaling pathways might be involved. To shed light on the action mechanism of arctigenin, this work investigated its effects on the activation of three important pathways (MAPKs, mTOR, and MLCK) which are relevant in the expression of TJ proteins . The results showed that arctigenin did not affect the activation of ERK, JNK and P38 induced by TNF‐α in colon epithelial cells, but inhibited the phosphorylation of mTOR, the expression of MLCK and phosphorylation of MLC.…”

Binding of Candida albicans to Human CEACAM1 and CEACAM6 Modulates the Inflammatory Response of Intestinal Epithelial Cells

“…Since C. albicans has the capacity of traversing the intestinal epithelial barrier and can also alter its permeability (27), and CEACAM1 expression also influences vascular (28, 29) and colonic (30) permeability, we next tested whether CEACAM1 knockdown affects the epithelial barrier function. All cell lines were grown on Transwell filters and tested for two permeability parameters: i.e., the ability to prevent the permeation of fluorescein isothiocyanate (FITC)-dextran and transepithelial electrical resistance (TEER).…”

“Candida AlbicansInteractions With The Host: Crossing The Intestinal Epithelial Barrier”

“…176 However, less is known about the direct regulation of the secretion of AMPs by C. albicans and the gut mycobiota. Interestingly, in this context, microarraybased transcriptomic analyses of intestinal epithelial cells interacting with C. albicans did not report overexpression of AMPs-related genes following infection, 177 whereas a strong expression of AMPs (especially DEFB4) was observed in oral cells challenged with the fungus. 177,178 Once more, these observations corroborate the view that molecular and cellular features characterizing C. albicans interactions depend on the type of host cell.…”