15-deoxy-delta(12-14)-prostaglandin-j2 and Colitis

Uncontrolled macrophage functions cause failure to resolve gut inflammation and has been implicated in the pathogenesis of inflammatory bowel disease (IBD). 15-Deoxy-Δ

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Colitis; Dextran Sulfate; Disease Models, Animal; Immunologic Factors; Intestinal Mucosa; Macrophages; Male; Mice; Prostaglandin D2; STAT3 Transcription Factor; Treatment Outcome

The selenoprotein glutathione peroxidase 2 (GPx2) is highly expressed in the gastrointestinal epithelium. During inflammatory bowel disease and colorectal cancer, GPx2 expression is enhanced.. We analyzed GPx2 expression and transcriptional regulation during the different phases of dextran sulfate sodium (DSS)-induced colitis in mice and in cytokine-treated colorectal cancer cells.. In the colon of DSS-treated mice, GPx2 was upregulated during the acute and recovery phase. In the latter, it was specifically localized in regenerating ki67-positive crypts next to ulcerations. In cultured cells, endogenous GPx2 expression and GPx2 promoter activity were enhanced by the anti-inflammatory mediators 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) and interleukin-22 (IL-22), while it was unaffected by classical proinflammatory cytokines like IL-1β. Induction of GPx2 expression by 15d-PGJ2 was mediated through Nrf2. In contrast, in DSS-treated Nrf2-KO mice GPx2 expression remained upregulated during recovery, which appeared to be independent of Nrf2. IL-22 activates transcription factors of the signal transducers and activators of transcription (STAT) family. Therefore, we analyzed the GPx2 promoter for putative STAT-responsive elements and identified 4 of them. Point mutation of the binding element next to the transcription start completely abolished promoter activation after IL-22 treatment and after cotransfection of STAT expression plasmids. To show in vivo relevance of the obtained results, we performed immunohistochemistry for phospho-STAT3 and GPx2. Especially during acute colitis, GPx2 and nuclear STAT3 colocalized in inflamed areas.. GPx2 is a novel target of STAT transcription factors. The upregulation of GPx2 by IL-22 indicates that GPx2 might be important for the resolution of inflammation.

Topics: Animals; Caco-2 Cells; Colitis; Colon; Cytokines; Dextran Sulfate; Glutathione Peroxidase; Humans; Immunologic Factors; Interleukin-22; Interleukins; Ki-67 Antigen; Mice; NF-E2-Related Factor 2; Promoter Regions, Genetic; Prostaglandin D2; STAT Transcription Factors; Up-Regulation

1. Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leukocyte infiltration, and increased expression of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) in the colon. Recent evidence also suggests that the cyclopentenone prostaglandin (PG) 15-deoxy-delta(12,14)-PGJ(2) (15d- PGJ(2)) functions as an early anti-inflammatory signal. 2. The aim of the present paper is to investigate the effects of 15d-PGJ(2) in rats subjected to experimental colitis. 3. Colitis was induced in rats by intra-colonic instillation of dinitrobenzene sulphonic acid (DNBS). 15d-PGJ(2) was administered daily as intraperitoneal injection (20 or 40 microg kg(-1)). On day 4, animals were sacrificed and tissues were taken for histological and biochemical analysis. 4. 15d-PGJ(2) significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. 15d-PGJ(2) also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde (MDA) and (iv) of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). 5. Furthermore, 15d-PGJ(2) reduced the increase in immunohistochemical staining for (i) inducible nitric oxide synthase (iNOS), (ii) nitrotyrosine and (iii) poly (ADP-ribose) polymerase (PARP), as well as (iv) the increased expression of ICAM-1 caused by DNBS in the colon. 6. Electrophoresis mobility shift assay (EMSA) of inflamed colon revealed that 15d- PGJ(2) also caused a substantial reduction of the activation of nuclear factor-kappaB (NF-kappaB). Furthermore, 15d-PGJ(2) stimulates the activation of heat shock protein 72 (hsp72) in the inflamed colon, as assessed by Western blot analysis. 7. In conclusion, 15d-PGJ(2) reduces the development of experimental colitis.

Topics: Animals; Benzenesulfonates; Colitis; Colon; Male; Prostaglandin D2; Rats; Rats, Sprague-Dawley

Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily originally shown to play a critical role in adipocyte differentiation and glucose homeostasis, has recently been implicated as a regulator of cellular proliferation and inflammatory responses. Colonic epithelial cells, which express high levels of PPAR-gamma protein, have the ability to produce inflammatory cytokines that may play a role in inflammatory bowel disease (IBD). We report 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. Moreover, thiazolidinedione ligands for PPAR-gamma markedly reduce colonic inflammation in a mouse model of IBD. These results suggest that colonic PPAR-gamma may be a therapeutic target in humans suffering from IBD.

Topics: Animals; Caco-2 Cells; Colitis; Cytokines; DNA-Binding Proteins; Epithelium; Gene Expression; HT29 Cells; Humans; I-kappa B Proteins; Inflammation; Inflammatory Bowel Diseases; Interleukin-8; Ligands; Mice; Microbodies; NF-kappa B; NF-KappaB Inhibitor alpha; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors