Cellular Retinoic Acid Bioavailability Determines Epithelial Integrity: Role of Retinoic Acid Receptor α Agonists in Colitis

  title={Cellular Retinoic Acid Bioavailability Determines Epithelial Integrity: Role of Retinoic Acid Receptor $\alpha$ Agonists in Colitis},
  author={Makoto Osanai and Nami Nishikiori and Masaki Murata and Hideki Chiba and Takashi Kojima and Norimasa Sawada},
  journal={Molecular Pharmacology},
  pages={250 - 258}
The epithelial barrier is determined primarily by intercellular tight junctions (TJs). We have demonstrated previously that all-trans retinoic acid (atRA) plays an important role in forming functional TJs through a specific retinoic acid receptor (RAR)/retinoid X receptor heterodimer in epithelial cells. However, the physiological relevance of retinoic acids (RAs) in maintaining the epithelial integrity remains to be examined. Here, we show that several types of RA, including atRA, promote the… 

Cellular retinoic acid bioavailability in various pathologies and its therapeutic implication

RA normalized retinal astrocytes that are compromised in diabetes, resulting in suppression of vascular leakiness and attenuated the loss of the epithelial barrier in murine experimental colitis, implying the potential feasibility of a therapeutic strategy targeting the stellate cell system.

Checkpoint Kinase 1 Activation Enhances Intestinal Epithelial Barrier Function via Regulation of Claudin-5 Expression

The results suggest that Chk1 activation by daunorubicin and rebeccamycin induced claudin-5 expression and enhanced TJ barrier function in Caco-2 cell monolayer, which suggests a link between DNA damage and TJ integrity in the human intestine.

Expression of claudins -2 and -4 and cingulin is coordinated with the start of stratification and differentiation in corneal epithelial cells: retinoic acid reversibly disrupts epithelial barrier

The results suggest that TJ assembly is tightly linked to the expression of corneal epithelial terminal phenotype, and TER increases mainly depend on TJ assembly.

Inhibitory effects of retinoic acid receptor alpha stimulants on murine cataractogenesis through suppression of deregulated calpains.

Results showed that a certain type of RA inhibits Ca(2+) elevation and subsequent overactivation of calpains, suggesting the potential feasibility of calpain-targeting therapies mediated by RA for cataract.

All Trans-Retinoic Acids Facilitate the Remodeling of 2D and 3D Cultured Human Conjunctival Fibroblasts

The findings reported in this study indicate that ATRA may exacerbate both superficial and vertical conjunctival fibrosis spreading independently of TGF-β2-induced changes.

Retinoic acid production by intestinal dendritic cells.

Retinoid Signaling in Intestinal Epithelial Cells Is Essential for Early Survival From Gastrointestinal Infection

Retinoid signaling in the IEC was crucial for the A– host to survive early infection following C. rodentium infection, and treating A– mice with retinoic acid beginning on the day of infection protects most mice from early lethality.

Alterations of Intercellular Junctions in Peritoneal Mesothelial Cells from Patients Undergoing Dialysis: Effect of Retinoic Acid

The HT monolayer has lower TER than LT, which might be associated with the peritoneal permeability in these patients, and ATRA might be a therapeutic alternative to maintain mesothelial integrity, since it improved TJ localization and expression.



Retinoid X Receptor α and Retinoic Acid Receptor γ Mediate Expression of Genes Encoding Tight-Junction Proteins and Barrier Function in F9 Cells during Visceral Endodermal Differentiation

It is shown that RA induces the TJ structure and expression of several TJ-associated molecules, as well as a barrier function in the genetically engineered cell line F9:rtTA:Cre-ERT L32T2, which allows sophisticated genetic manipulations simply by addition of ligands.

Expression from the human occludin promoter is affected by tumor necrosis factor α and interferon γ

Experimental evidence in transfection assays shows that this interaction is essential for targeting occludin to the tight junction in cells lacking endogenous occlUDin, although C-terminally truncated Occludins are inserted into tight junctions that contain intact occluda by lateral association.

cDNA Cloning of Human Retinoic Acid-metabolizing Enzyme (hP450RAI) Identifies a Novel Family of Cytochromes P450 (CYP26)*

It is demonstrated that hP450RAI is responsible for generation of several hydroxylated forms of RA, including 4-OH, 4-oxo-RA, and 18-OH-RA and concluded that this enzyme plays a key role in RA metabolism, functioning in a feedback loop where RA levels are controlled in an autoregulatory manner.

Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells

It is suggested that INFγ/TNFα and IL-13 have differential effects on CL 2, 3 and 4 in tight junctions, which may lead to increased permeability via different mechanisms.

Significance of anti-inflammatory effects of PPARγ agonists?

PPARγ mediated effects in the experimental setting of toll-like receptor stimulation were independent of NFκB and interferon regulatory factor, in contrast with GR action, which indicates that glucocorticoids and ligands of PPARγ could have additive therapeutic effects.

Expression of the Retinoic Acid-Metabolizing Enzyme CYP26A1 Limits Programmed Cell Death

It is shown that various cell lines overexpressing CYP26A1, a cytochrome P450 enzyme specifically involved in the catabolic inactivation of RA, exhibit increased resistance to various apoptogenic factors, including death receptor ligands such as tumor necrosis factor-related apoptosis-inducing ligand.

Epigenetic silencing of occludin promotes tumorigenic and metastatic properties of cancer cells via modulations of unique sets of apoptosis-associated genes.

It is suggested that methylator phenotype of occlUDin provides enhanced tumorigenic, invasive, and metastatic properties of cancer cells, identifying occludin as a likely candidate for a tumor-suppressor gene in certain types of cancer.

A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response.

It is reported here that PPAR-gamma ligands dramatically attenuate cytokine gene expression in colon cancer cell lines by inhibiting the activation of nuclear factor-kappaB via an IkappaB-alpha-dependent mechanism, and thiazolidinedione ligands for PPARS markedly reduce colonic inflammation in a mouse model of IBD.

Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis.

These studies provide insight into tissue microenvironmental changes during model inflammatory bowel disease and identify HIF-1 as a critical factor for barrier protection during mucosal insult.