Therapeutic effects of interleukin-4 gene transfer in experimental inflammatory bowel disease (original) (raw)
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Proinflammatory properties of IL-4 in the intestinal microenvironment
AJP: Gastrointestinal and Liver Physiology, 2005
IL-4 is involved in type 2 T helper cell (Th)2-type immune responses and, in some cases, can promote Th1 responses. However, the proinflammatory potential of IL-4 alone is unclear. In this study, we examined the ability of IL-4 to induce colitis after its overexpression in the colon using an adenoviral vector (Ad5) and compared results with those obtained after overexpression of IL-12, a cytokine implicated in several models of colitis. Overexpression of IL-4 or IL-12 caused a fatal colitis within 24 h in 60% of animals and was dose and strain dependent. IL-12-induced colitis was accompanied by the local expression of IFN-γ and TNF-α but not IL-4 mRNA and protein. Conversely, IL-4-induced colitis was accompanied by the local expression of IL-4 and TNF-α but not IFN-γ mRNA and protein. The Ad5-IL4-induced colitis did not persist beyond 3 days and was present in recombinase activation gene-2 (RAG-2)−/− mice but not in STAT6−/− mice. Acute lethal colitis induced by Ad5IL12 was T cell m...
Pathophysiological role of nitric oxide in rat experimental colitis
International Journal of Immunopharmacology, 1998
Overproduction of nitric oxide "NO# by inducible nitric oxide synthase "iNOS# may contribute to the pathophysiology of ulcerative colitis[ A 1\3\5!trinitrobenzenesulfonic acid sodium salt "TNBS# colitis model was established to examine the e}ect of selective iNOS inhibition\ by S!"1!aminoethyl# isothiouronium bromide "ITU#\ on colonic mucosal cell damage and in~ammation[ Rats\ killed 6 days after TNBS\ had increased colonic mucosal levels of iNOS and interleukin!7 "IL!7#\ in addition to severe colonic in~ammation which was characterized by signi_cantly increased colon weight\ damage score and colonic myeloperoxidase activity "MPO# "a marker of neutrophil in~ux#[ TNBS!treated rats had markedly decreased body weight and thymus weight[ Administration of colitic rats with ITU signi_cantly inhibited iNOS activity:expression and tended to reduce mucosal levels of IL!7\ but no e}ect on MPO activity was observed[ Following ITU therapy\ colitic rats had reduced colonic damage and losses in body weight and thymus weight were reversed[ Improvement of TNBS colitis by ITU suggested that excess NO\ produced by iNOS\ may have contributed to the initiation: ampli_cation of colonic disease\ by mechanisms including enhancement of IL!7 release NO!mediated enhancement of pro!in~ammatory cytokine release was further investigated in vitro[ Lipo! polysaccharide "LPS# and interferon!g "IFN!g# stimulated release of nitrite\ lactate dehydrogenase "LDH#\ TNFa\ IL!0b and IL!7 from rat peritoneal macrophages\ all of which were signi_cantly reduced by ITU[ This suggests that NO!mediated cell damage enhances pro!in~ammatory mediator release from macrophages[ In addition\ enhancement of IL!7 and TNFa release was also partially NO!dependent in activated peritoneal neutrophils[ Therefore\ the amelioration of TNBS colitis by ITU could include inhibition of NO!mediated pro!in~ammatory cytokine release[ Þ 0887 International Society for Immunopharmacology[ Keywords] colitis\ trinitrobenzene sulfonic acid\ nitric oxide\ inducible nitric oxide synthase\ tumour necrosis factor\ interleukin!0\ interleukin!7
Induction of iNOS in a rat model of acute colitis
1999
Induction of colitis by 2,4,6-Trinitrobenzenesulphonic acid (TNB) in the rat is a widely used experimental model of inflammatory bowel disease. Action of TNB as a hapten, induces colitis involving infiltration of colonic mucosa by neutrophils and macrophages and increased production of inflammatory mediators. The aim of the present study was to measure nitric oxide synthase (NOS) activity and characterize relations between inducible NOS (iNOS) activity and other signs of inflammation in TNB-induced colitis. A profound and sustained increase in the activity of iNOS was found in the colon. The activity of NOS in the spleen was also increased, but remained at low levels as compared to those in colon. No increases in plasma nitrite + nitrate concentrations were found suggesting local rather than systemic induction of iNOS. The increase in iNOS activity in the colon was preceded by macroscopic inflammatory lesions, like hyperemia, ulcerations and edema formation as well as neutrophil accumulation in the gastric mucosa and increased circulating concentrations of PGE2 metabolite (PGEM). Concentrations of PGEM in the plasma and myeloperoxidase activity (MPO; marker of neutrophil infiltration) in the gut declined in 48h whereas increased iNOS activity and the macroscopic inflammatory lesions remained over the 72h follow-up period. The results demonstrate increased local iNOS activity in TNB-induced colitis mimicking the situation in human inflammatory bowel disease.
2005
Genetic deficiency in the expression of interleukin-10 (IL-10) is associated with the onset and progression of experimental inflammatory bowel disease (IBD). The clinical significance of IL-10 expression is supported by studies showing that immune-augmentation of IL-10 prevents inflammation and mucosal damage in animal models of colitis and in human colitis. Interleukin-10 (IL-10), an endogenous anti-inflammatory and immunomodulating cytokine, has been shown to prevent some inflammation and injury in animal and clinical studies, but the efficacy of IL-10 treatment remains unsatisfactory. We found that intra-peritoneal administration of adenoviral IL-10 to mice significantly reversed colitis induced by administration of 3% DSS (dextran sulfate), a common model of colitis. Adenoviral IL-10 (Ad-IL10) transfected mice developed high levels of IL-10 (394 +/-136 pg/ml) within the peritoneal cavity where the adenovirus was expressed. Importantly, when given on day 4 (after the induction of colitis w/DSS), Ad-IL10 significantly reduced disease activity and weight loss and completely prevented histopathologic injury to the colon at day 10. Mechanistically, compared to Ad-null and DSS treated mice, Ad-IL10 and DSStreated mice were able to suppress the expression of MAdCAM-1, an endothelial adhesion molecule associated with IBD. Our results suggest that Ad-IL10 (adenoviral IL-10) gene therapy of the intestine or peritoneum may be useful in the clinical treatment of IBD, since we demonstrated that this vector can reverse the course of an existing gut inflammation and markers of inflammation.
Human Gene Therapy, 2000
Inflammatory bowel disease (IBD) comprises the two disorders ulcerative colitis (UC) and Crohn's disease (CD). Although the etiology is still unclear, initiation and aggravation of the inflammatory processes seem to be due to a massive local mucosal immune response. An increased number of greatly activated macrophages seems to contribute to the onset of IBD by expressing upregulated costimulatory molecules (e.g., CD80/CD86) and a cytokine profile favouring a type I proinflam matory response. The release of interleukin 2 (IL-2) and Interferon-c (IFN-c) by naive T lymphocytes predominantly stimulates cytotoxic T lymphocytes, macrophages, and natural killer (NK) cells and increases the antigen-presenting potential of all these cell types. Opposite this proinflammatory immune reaction a compensatory type II antiinflam matory response has been suggested in the inflamed mucosa, involving mainly interleukin 4 and interleukin 10. Both cytokines are able to downregulate inflammatory mediators including tumor necrosis factor-a (TNF-a) and interleukin 1 and favor a humoral immune response. The main goal of this clinical trial is the local liposom e-mediated gene transfer of these two antiinflam matory cytokines, interleukin 4 and interleukin 10, in patients with severe IBD of the rectum. This local administration of antiinflam matory cytokines will avoid toxic systemic side effects, prevents blocking of the beneficial effects of proinflam matory cytokines, e.g., TNF-a in other tissue compartments and increases the local concentration of interleukin 4 and interleukin 10 over a prolonged period of time. The combined effects of IL-4 and IL-10 have been shown to shift the Th1/Th2 cell activation in favor of a Th2 immune response which seems to be essential for fighting against the inflammation and ultimative healing.
Sequential release of cytokines, lipid mediators and nitric oxide in experimental colitis
Mediators of Inflammation, 1995
The object of this study was to establish whether different pro- and anti-inflammatory mediators were formed in colonic tissue from experimental colitis depending on the course of the disease. Concentrations of mediators of inflammation were examined in colonic tissue in dextran induced colitis in mice. Initial inflammation was produced by 5 days treatment of 10% dextran sodium sulfate (DSS) in drinking water, followed by a further 9 day period of 2% DSS in an attempt to produce a milder chronic inflammation. The degree of inflammation was scored by a standardized macroscopic and histological examination. Initially, a 60% maximum inflammation score was observed at day 4. At this time inflammation was associated with the release of interleukin-lβ (IL-1β) and tumour necrosis factor-α (TNFα), whereas both prostaglandins 6kPGF1αand PGE2and nitric oxide (NO) markedly decreased. Then a 25% inflammation score was reached which coincided with an increased production of platelet-activating f...
Gut, 1998
Background-Nitric oxide (NO) synthesis and inducible nitric oxide synthase (iNOS) expression are increased in colonic biopsy specimens from patients with ulcerative colitis, but the cellular source of NO production is not known. Aims-To examine the distribution of iNOS in human colonic mucosa and to explore the ability of T lymphocyte derived cytokines to regulate iNOS expression and activity in human colonic epithelial cells. Methods-iNOS expression was examined using immunohistochemistry in colonic biopsy samples from 12 patients with ulcerative colitis and three with infectious colitis and compared with 10 normal controls. In vitro iNOS expression and activity were determined in HT-29 cell cultures; nitrite levels were measured using a fluorescent substrate, iNOS mRNA expression by northern blot analysis, and iNOS protein expression by western blot analysis. Results-No iNOS expression was detected (10 of 10) in non-inflamed mucosa derived from normal controls. In 11 of 12 cases of newly diagnosed ulcerative colitis, iNOS protein was expressed in the epithelial cells, while no other positive cells were found in the lamina propria. Similar iNOS labelling was found in colonic biopsy samples from patients with infectious colitis in the acute phase, but when reexamined in samples from patients in total remission, no iNOS staining was observed. Both interleukin (IL)-13 and IL-4, but not IL-10, are potent inhibitors of iNOS expression and activity induced by an optimal combination of cytokines, namely IL-1 , tumour necrosis factor and interferon. Conclusions-The data suggest that the epithelium is the major source of iNOS activity in ulcerative colitis and that IL-13 and IL-4 may act as intrinsic regulators of NO generation in intestinal inflammation.
Comparison of two models of inflammatory bowel disease in rats
Advances in clinical and experimental medicine : official organ Wroclaw Medical University, 2018
There is a need for experimental animal models for inflammatory bowel diseases (IBD), but no proposed model has been unanimously accepted. The aim of this study was to develop 2 affordable models of IBD in rats and to compare them. We produced IBD in rats using either dextran sodium sulfate (DSS) or 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). The requirements for experimental models were: a predictable clinical course, histopathology and inflammation similar to human ulcerative colitis (UC) and Crohn's disease (CD). The effect of acute administration of DSS and TNBS on oxidative stress (as measured by the assessment of glutathione peroxidase - GPx) was verified. The activity of whole blood GPx was measured using a commercially available Randox kit (Crumlin, UK). The administration of DSS increased GPx activity compared to the control and TNBS-treated groups, but not to a statistically significant degree. Histological examination of the colonic mucosa following the administrati...