tretinoin and Ileitis

Retinoic acid (RA), produced by intestinal epithelial cells (IECs) and dendritic cells (DCs) promotes the induction of regulatory T cells (Tregs) and decreases the induction of T-helper (Th)17 cells.. We studied the roles of RA in mice that overproduce tumor necrosis factor (TNF) and develop chronic ileitis (TNF_ARE mice). We assessed the frequency and function of CD103+ DCs, Th17 cells, and Tregs by flow cytometry, and we measured expression of cytokines and retinaldehyde dehydrogenase (RALDH) enzymes in ileum samples, DCs, and IECs by real-time polymerase chain reaction. We quantified RA by electrochemical analysis and examined the effect of RA supplementation on TNF-induced ileitis using histologic, coculture, and suppression assays and flow cytometry.. Numbers of CD103+ DCs decreased in the inflamed ilea of mice with chronic disease; RA synthetic machinery (RALDH1,2) was down-regulated. Nevertheless, the proportion of CD4+, CD25+, FoxP3+ Tregs increased, indicating an alternate source for RA. IECs responded to reduced levels of RA by up-regulating RALDH3 in vivo and in vitro. Net tissue levels of RA remained lower in TNF+ARE than wild-type mice, indicating that epithelial up-regulation of RALDH3 could not maintain adequate concentrations of RA, probably because of loss of IEC mass. RA supplementation significantly attenuated disease by increasing the number and function of CD103+ DCs and Tregs and reducing Th17 cells.. Reduced levels of RA appear to induce IECs to up-regulate synthesis of RA. RA supplementation attenuates ileitis through its effects on CD103+ DCs, Tregs, and Th17 cells. RA supplementation might offer therapeutic benefit in Crohn's disease.

Topics: Animals; Antigens, CD; Cell Proliferation; Cells, Cultured; Coculture Techniques; Cytokines; Dendritic Cells; Disease Models, Animal; Forkhead Transcription Factors; Ileitis; Integrin alpha Chains; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; T-Lymphocytes, Regulatory; Th17 Cells; Tretinoin

Aberrant leukocyte migration has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Lemon grass is a natural herb that contains citral, which suppresses lymphocyte expression of gut homing molecules by inhibiting retinoic acid formation. We therefore hypothesized that lemon grass intake could ameliorate excess migration of leukocytes to the inflamed intestine in chronic ileitis.. Migration of fluorescence-labeled T cells to microvessels in the ileal mucosa of SAMP1/Yit mice was monitored using intravital microscopy. In some mice, lemon grass solution was administered for two weeks. For evaluation of the effects on chronic ileitis, mice were treated with lemon grass for 26 weeks.. Surface expression of beta7 and CCR9 on T lymphocytes was stronger in SAMP1/Yit mice than in AKR/J mice. Lemon grass treatment attenuated the surface expression of beta7-integrin and CCR9. The number of adherent lymphocytes to microvessels in chronic inflamed ileum was significantly few when lymphocytes were isolated from lemon grass treated mice. Long-term lemon grass treatment improved ileitis in SAMP1/Yit mice, which was assessed by body weight, histological changes and the infiltration of beta7-positive cells.. Lemon grass ameliorated ileitis through decreasing lymphocyte migration by inhibiting beta7-expression, suggesting its therapeutic usefulness for IBD.

Topics: Alcohol Oxidoreductases; Animals; Cell Movement; Cymbopogon; Ileitis; Ileum; Integrin beta Chains; Intestinal Mucosa; Mice; Mice, Inbred AKR; Microscopy, Fluorescence; Microvessels; Phytotherapy; Receptors, CCR; RNA, Messenger; T-Lymphocytes; Tretinoin

The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. Chemokine receptor 9 (CCR9) is a chemokine receptor known to be central for migration of immune cells into the intestine. Its only ligand, CCL25, is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation. To date, there are no reports of small-molecule antagonists targeting CCR9. We report, for the first time, the discovery of a small molecule, CCX282-B, which is an orally bioavailable, selective, and potent antagonist of human CCR9. CCX282-B inhibited CCR9-mediated Ca(2+) mobilization and chemotaxis on Molt-4 cells with IC(50) values of 5.4 and 3.4 nM, respectively. In the presence of 100% human serum, CCX282-B inhibited CCR9-mediated chemotaxis with an IC(50) of 33 nM, and the addition of α1-acid glycoprotein did not affect its potency. CCX282-B inhibited chemotaxis of primary CCR9-expressing cells to CCL25 with an IC(50) of 6.8 nM. CCX282-B was an equipotent inhibitor of CCL25-directed chemotaxis of both splice forms of CCR9 (CCR9A and CCR9B) with IC(50) values of 2.8 and 2.6 nM, respectively. CCX282-B also inhibited mouse and rat CCR9-mediated chemotaxis. Inhibition of CCR9 with CCX282-B results in normalization of Crohn's disease such as histopathology associated with the TNF(ΔARE) mice. Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic/pharmacodynamic relationship for CCR9 antagonists in the treatment of intestinal inflammation.

Topics: Administration, Oral; Animals; Calcium; Cell Line; Chemotaxis, Leukocyte; Crohn Disease; Gastrointestinal Agents; Humans; Ileitis; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Radioligand Assay; Rats; Receptors, CCR; Sulfonamides; T-Lymphocytes; Tretinoin; Tumor Necrosis Factor-alpha

Topics: Abnormalities, Drug-Induced; Corneal Opacity; Humans; Ileitis; Isotretinoin; Pseudotumor Cerebri; Tretinoin; Uric Acid