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PubMed1998

Nutrition in inflammatory bowel disease.

Nutrition is clearly disturbed by active intestinal inflammation. Appetite is reduced, yet energy substrates are diverted into the inflammatory process, and thus weight loss is characteristic. The nutritional disturbance represents part of a profound defect of somatic function. Linear growth and pubertal development in children are notably retarded, body composition is altered, and there may be significant psychosocial disturbance. Macrophage products such as tumour necrosis factor-alpha and interleukins-1 and 6 may be the central molecules that link the inflammatory process to this derangement of homeostasis. Intriguingly, there is also increasing evidence that an aggressive nutritional programme may in itself be sufficient to reduce the mucosal inflammatory response. Recent evidence suggests that enteral nutrition alone may reduce many pro-inflammatory cytokines to normal and allow mucosal healing. In addition, specific nutritional components, such as n-3 polyunsaturated fatty acids, may have an anti-inflammatory effect as they may alter the pattern of leukotrienes generated during the immune response. The recent discovery of the specific molecular mediators of appetite and body composition, such as leptin and myostatin, may allow increased therapeutic specificity and further improvement in the nutritional treatment of the inflammatory bowel diseases.

Body Composition↗
PubMed2006

Thermal degradation of the Fusarium mycotoxin deoxynivalenol.

Deoxynivalenol (DON) is a toxic secondary metabolite produced by molds of the Fusarium genus, which are able to infect cereal crops in the field. Concerning its rate of occurrence and mean concentration, DON is one of the most important mycotoxins in cereal commodities. Its toxic effects range from causing diarrhea, vomiting, and gastro-intestinal inflammation to noncompetitive inhibition of the biosynthesis of proteins in eukaryotic cells. To study the stability of DON under food-processing conditions such as cooking or baking, we performed model heating experiments and screened the residue for degradation products. Heating of DON and 3-acetyldeoxynivalenol (3-AcDON), especially under alkaline conditions, gave a mixture of compounds, which were isolated and structurally elucidated by NMR and MS experiments. Three of these compounds were already known (norDON A, norDON B, and norDON C), while four were new and named 9-hydroxymethyl DON lactone, norDON D, norDON E, and norDON F. The significance of the DON degradation products was checked by analyzing commercially available food samples. norDON A, B, and C were detected in 29-66% of the samples in mean concentrations ranging from 3 to 15 microg/kg. Furthermore, cell culture experiments using IHKE cells showed that the compounds that were detected in food samples are less cytotoxic in the formazan dye cytotoxicity assay compared to DON. Whereas DON revealed a median effective concentration (EC50) at 1.1 micromol/L, all other compounds did not show any significant effect up to 100 micromol/L. These findings indicate that the degradation of DON under thermal treatment might reduce the toxicity of DON contaminated food.

Cell Line, Transformed↗
PubMed2000

Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism.

It has been reported that measles virus may be present in the intestine of patients with Crohn's disease. Additionally, a new syndrome has been reported in children with autism who exhibited developmental regression and gastrointestinal symptoms (autistic enterocolitis), in some cases soon after MMR vaccine. It is not known whether the virus, if confirmed to be present in these patients, derives from either wild strains or vaccine strains. In order to characterize the strains that may be present, we have carried out the detection of measles genomic RNA in peripheral mononuclear cells (PBMC) in eight patients with Crohn's disease, three patients with ulcerative colitis, and nine children with autistic enterocolitis. As controls, we examined healthy children and patients with SSPE, SLE, HIV-1 (a total of eight cases). RNA was purified from PBMC by Ficoll-paque, followed by reverse transcription using AMV; cDNAs were subjected to nested PCR for detection of specific regions of the hemagglutinin (H) and fusion (F) gene regions. Positive samples were sequenced directly, in nucleotides 8393-8676 (H region) or 5325-5465 (from noncoding F to coding F region). One of eight patients with Crohn disease, one of three patients with ulcerative colitis, and three of nine children with autism, were positive. Controls were all negative. The sequences obtained from the patients with Crohn's disease shared the characteristics with wild-strain virus. The sequences obtained from the patients with ulcerative colitis and children with autism were consistent with being vaccine strains. The results were concordant with the exposure history of the patients. Persistence of measles virus was confirmed in PBMC in some patients with chronic intestinal inflammation.

Adult↗
PubMed2000

Influence of disease site and activity on peripheral neutrophil function in inflammatory bowel disease.

Reactive oxygen species, released by phagocytes, are involved in tissue injury in inflammatory bowel diseases. The aim of our study was to evaluate peripheral neutrophil function in patients with ulcerative colitis (N = 66) and Crohn's disease (N = 62) with respect to disease activity and extent, using chemiluminometry after three stimuli. Twenty-seven healthy subjects were enrolled as controls. Neutrophils from ulcerative colitis and Crohn's disease patients had a significantly higher response than those from controls following phorbol myristate acetate (86.6 +/- 6.5, 173.8 +/- 11.9, 167.5 +/- 12.2 mV, P < 0.0001), formyl-methionyl-leucyl-phenylalanine (39.5 +/- 3.4, 41.3 +/- 2.7, 58.6 +/- 4.7 mV, P < 0.001), and zymosan (142.6 +/- 10.4, 223.7 +/- 8.9, 231.2 +/- 9.5 mV, P < 0.0001) administration. The increased response was observed during both active disease and remission. The highest chemiluminescence values were found in patients with active ulcerative pancolitis and ileal Crohn's disease. The activation of circulating neutrophils may indicate persistent intestinal inflammation or may be triggered by luminal factors even in the absence of symptoms.

Adult↗
PubMed1998

Plasma and mucosal fatty acid pattern in colectomized ulcerative colitis patients.

Patients with inflammatory bowel disease (IBD) have increased plasma n3 polyunsaturated fatty acids (PUFAs), which in ulcerative colitis (UC) patients persists six months after colectomy, suggesting a primary abnormality in fatty acid (FA) metabolism in IBD. This finding needed to be confirmed in a larger series of UC long-term colectomized patients. We aimed to assess the plasma FA pattern in UC colectomized patients with either Brooke's ileostomy (UC-BI) or ileal pouch anal anastomosis (UC-IPAA) and the mucosal FA pattern in the ileal reservoir of the UC-IPAA patients. Plasma FAs were assessed in 63 UC colectomized patients (31 with BI and 32 with IPAA) and 30 controls. In 26 UC-IPAA (8 with pouchitis and 18 without pouchitis) and in 13 healthy controls gut mucosal FAs were also investigated. FAs were detected by capillary column gas-liquid chromatography. Increased levels of saturated fatty acids (SFAs) and decreased percentages of monounsaturated fatty acids (MUFAs) were observed in both groups of patients. There were no changes in plasma n3 and n6 PUFAs. The mucosal FA pattern of the ileal reservoir consisted of increased long-chain PUFAs, specially n6 PUFA, and a decrease of their essential precursors. High percentages of SFAs and low percentages of MUFAs were also seen. The plasma FA profile previously described in IBD is not observed long-term after colectomy in UC, suggesting that it is related with the presence of inflamed intestine. High concentrations of SFAs and decreased percentages of MUFAs might represent early events in disturbed FA metabolism in IBD. The changes in FAs of the ileal reservoir, which closely resemble those found in human and experimental IBD, probably represent a common pattern of intestinal inflammation.

Adult↗
PubMed2004

IL-10 gene therapy is therapeutic for dextran sodium sulfate-induced murine colitis.

The transfer of genes encoding immunoregulatory proteins is a promising new strategy in the treatment of intestinal inflammation. Previous work has demonstrated that daily systemic interleukin (IL)-10 therapy is able to prevent disease onset in animal models of colitis but is not sufficient to treat established disease. This study investigates the therapeutic efficacy of an adenovirus encoding IL-10 (AdvmuIL-10) in the treatment of experimental colitis. Colitis was induced in BALB/c mice by the addition of dextran sodium sulfate to the drinking water for 7 days. A single systemic injection of AdvmuIL-10, empty cassette vector (Adv0), or saline vehicle was administered on day 4 after the onset of colitis. The addition of DSS to the drinking water led to an acute, dose-dependent colitis. A single injection of AdvmuIL-10 led to a marked reduction in both stool markers of inflammation (IL-1beta, IL-6, and TNFRII) and serum IL-6. Furthermore, the histological colitis score was significantly reduced in mice receiving AdvmuIL-10 compared to controls (4.9 +/- 1.1 Vs 9.1 +/- 1.2, respectively; P < 0.05). A single systemic injection of AdvmuIL-10 is therapeutic in mice with established DSS colitis. Gene therapy strategies using adenoviral vectors encoding IL-10 may prove to be a potent therapy for chronic inflammation of the colon such as Crohn's disease.

Adenoviridae↗
PubMed2006

hPepT1 mediates bacterial tripeptide fMLP uptake in human monocytes.

Here, we examined hPepT1 expression in the monocytic cell line, KG-1. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that hPepT1 is expressed in KG-1 cells, while cDNA cloning and direct sequencing confirmed the sequence of KG-1 hPepT1 (accession number, AY634368). Immunoblotting of cell lysates from KG-1 cells or macrophages isolated from human peripheral blood revealed a approximately 100 kDa immunoreactive band mainly present in the membrane fraction. Uptake experiments showed that the transport of 20 microM radiolabeled Gly-Sarcosine ([14C]Gly-Sar) in KG-1 cells was Na+, Cl- dependent and disodium 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS)-sensitive. In addition, hPepT1 activity was likely to be coupled to a Na+/H+ exchanger, as evidenced by the fact that [14C]Gly-Sar uptake was not affected by the absence of Na+ when cells were incubated at low pH (5.2). Interestingly, hPepT1-mediated transport was reduced in KG-1 cells incubated at low pH as it was also observed in nonpolarized Caco2-BBE cells. This pattern of pH-dependence is due to a disruption of the driving force of hPepT1-mediated transport events. This was supported by our finding that nonpolarized cells, Caco2-BBE cells and KG-1 cells, have an increased permeability to H+ when compared to polarized Caco2-BBE cells. Finally, we showed that hPepT1 is responsible for transporting fMLP into undifferentiated and differentiated (macrophage-like) KG-1 cells. Together, these results show that hPepT1 is expressed in nonpolarized immune cells, such as macrophages, where the transporter functions best at the physiological pH 7.2. Furthermore, we provide evidence for hPepT1-mediated fMLP transport, which might constitute a novel immune cell activation pathway during intestinal inflammation.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2005

Diarrhea caused by primarily non-gastrointestinal infections.

Infectious diseases that do not primarily affect the gastrointestinal tract can cause severe diarrhea. The pathogenesis of this kind of diarrhea includes cytokine action, intestinal inflammation, sequestration of red blood cells, apoptosis and increased permeability of endothelial cells in the gut microvasculature, and direct invasion of gut epithelial cells by various infectious agents. Of the travel-associated systemic infections presenting with fever, diarrhea occurs in patients with malaria, dengue fever and SARS. Diarrhea also occurs in patients with community-acquired pneumonia, when it is suggestive of legionellosis. Diarrhea can also occur in patients with systemic bacterial infections. In addition, although diarrhea is rare in patients with early Lyme borreliosis, the incidence is higher in those with other tick-borne infections, such as ehrlichiosis, tick-borne relapsing fever and Rocky Mountain spotted fever. Unfortunately, it is often not established whether diarrhea is an initial symptom or develops during the course of the disease. The real incidence of diarrhea in some infectious diseases must also be questioned because it could represent an adverse reaction to antibiotics.

Diarrhea↗
PubMed2002

Caprylic acid and medium-chain triglycerides inhibit IL-8 gene transcription in Caco-2 cells: comparison with the potent histone deacetylase inhibitor trichostatin A.

1. Medium-chain triglyceride (MCT) is often administered to patients with Crohn's disease (CD) or short-bowel syndrome. However, little is known about the effects of medium-chain fatty acids (MCFAs) and MCT on intestinal inflammation. In this study we examined whether caprylic acid, one of the MCFAs, and MCT suppress IL-8 secretion by differentiated Caco-2 cells. 2. We found for the first time that caprylic acid and MCT suppress IL-8 secretion by Caco-2 cells at the transcriptional level when precultured together for 24 h. We also tried to clarify the mechanism of IL-8 gene inhibition by examining the activation of NF-kappaB and other transcription factors by electrophoretic mobility shift assay (EMSA), and found that caprylic acid did not modulate their activation. 3. The result of dual-luciferase assay using Caco-2 cells transfected with IL-8 promoter/luciferase reporter plasmid revealed that caprylic acid inhibited the activation of IL-8 promoter. 4. Similar results were observed when cells were precultured with the well-known potent histone deacetylase inhibitor trichostatin A (TSA). 5. We examined the state of H4 acetylation in IL-8 promoter using the technique known as chromatin immunoprecipitation (Chr-IP). TSA rapidly induced H4 acetylation in IL-8 promoter chromatin, whereas caprylic acid did not. These results suggest that the inhibition of IL-8 gene transcription induced by caprylic acid and TSA does not necessarily require the marked suppression of transcription factors, and the mechanism of inhibition of IL-8 gene transcription may be different between caprylic acid and TSA.

Caco-2 Cells↗
PubMed2002

Substance P-stimulated interleukin-8 expression in human colonic epithelial cells involves Rho family small GTPases.

Interaction of the neuropeptide substance P (SP) and its neurokinin-1 receptor (NK-1R) plays an important role in the pathophysiology of intestinal inflammation. SP is known to stimulate production of interleukin (IL)-6 and IL-8 in the U-373-MG human astrocytoma cell line via activation of p38 MAPK (mitogen-activated protein kinase) and nuclear factor (NF)-kappaB, respectively. However, the signalling mechanisms by which SP-NK-1R interaction induces NF-kappaB activation and IL-8 expression are still not clear. In this study we demonstrate that SP stimulates IL-8 secretion and IL-8 promoter activity in the NCM460 non-transformed human colonic epithelial cell line transfected with NK-1R cDNA. Our results indicate that inhibition of endogenous Rho family proteins (RhoA, Rac1 and Cdc42) by their respective dominant negative mutants significantly decreases SP-induced IL-8 secretion and IL-8 promoter activity. We also demonstrate that SP rapidly activates RhoA, Rac1 and Cdc42 and that co-expression of the dominant negative mutants of RhoA, Rac1 and Cdc42 in NK-1R cDNA-transfected NCM460 cells significantly inhibits SP-induced NF-kappaB-dependent gene expression. These results demonstrate that Rho family small GTPases RhoA, Rac1 and Cdc42 are novel signal transducers for SP-stimulated IL-8 expression.

Cells, Cultured↗
PubMed1997

Regulation of platelet-activating factor receptor gene expression in vivo by endotoxin, platelet-activating factor and endogenous tumour necrosis factor.

A competitive PCR assay was developed to quantify platelet-activating factor (PAF) receptor (PAF-R) transcripts in rat tissues using a synthetic RNA as a competitor. We found PAF-R mRNA constitutively expressed in the eight organs tested, with the ileum containing the highest concentration [(3.49+/-0.15) x 10(7) molecules/microg of RNA]. Significant but lower levels were also detected in the jejunum, spleen, lungs, kidneys, heart, stomach and liver. Furthermore we defined the regulatory role of inflammatory mediators in ileal PAF-R gene expression using a rat model of intestinal injury induced by PAF or lipopolysaccharide (LPS). Injection of LPS or low-dose PAF resulted in a marked increase in ileal PAF-R mRNA within 30 min. The up-regulation on PAF-R elicited by PAF was biphasic, peaking first at 90 min, then again at 6 h. In contrast, LPS elicited a weak monophasic response. The second phase of PAF-R mRNA increase after PAF administration was completely abolished by WEB 2170, a PAF antagonist, and partially inhibited by antitumour necrosis factor (TNF) antibody. These observations indicate the involvement of endogenous PAF and TNF in this event. In conclusion, we found: (a) preferential PAF-R expression in the ileum, suggesting a role for PAF in intestinal inflammation; (b) induction of PAF-R expression in vivo by its own agonist; (c) a complex regulation of PAR-R gene expression in vivo involving a network of various pro-inflammatory mediators.

Animals↗
PubMed2001

Inflammatory bowel disease: pathogenesis and targets for therapeutic interventions.

Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases (IBDs) with a chronic relapsing course. The aetiology of these diseases remains unknown, but in the last decade an increase in experimental models of IBD has led to expansion of our understanding in various aspects of the aetiology and pathogenic mechanisms of IBD. A growing body of evidence coming from these models indicates that an immune response against gut constituents is of critical importance for intestinal inflammation and the subsequent destruction of the mucosa. For this reason, research on IBD has focused intensely on the immune and non-immune cell subsets as well as the soluble mediators involved in normal and dysregulated immune responses. An appreciation of the current knowledge of the pathogenesis of IBD is of paramount importance for the understanding of current, and development of new, treatment modalities.

Animals↗
PubMed1997

Furazolidone, amoxycillin, bismuth triple therapy for Helicobacter pylori infection.

BACKGROUND: Metronidazole-resistant Helicobacter pylori are generally the rule in developing countries such as Colombia. Developing countries need an effective, simple and inexpensive non-metronidazole therapy for H. pylori infection. AIM: To evaluate the combination of bismuth, furazolidone and amoxycillin for the treatment of H. pylori infection in Colombia. METHODS: Thirty patients with histologically documented H. pylori infection received the combination of bismuth subcitrate 240 mg b.d., furzolidone 100 mg q.d.s. and amoxycillin 500 mg q.d.s. for 14 days. Four or more weeks after ending therapy patients were re-endoscoped and gastric biopsies were obtained and examined using the Genta stain. Each slide was scored for presence, absence and density of H. pylori, active and chronic inflammation, intestinal metaplasia, erosions and atrophy. Cure was defined as the absence of H. pylori. RESULTS: All patients completed the course of therapy. Twenty-five patients were cured (86%, 95% CI: 65-94%). Mild, well-tolerated side-effects were reported by six patients (20%). CONCLUSIONS: This combination of bismuth, furazolidone and amoxycillin fulfills the criteria for successful H. pylori therapy and appears particularly well suited for developing countries since it is simple, inexpensive and effective. Furazolidone-containing therapies may become especially useful in the face of a world-wide increase in H. pylori resistance to metronidazole and macrolides.

Adult↗
PubMed1998

Antiinflammatory actions of cat's claw: the role of NF-kappaB.

BACKGROUND: Uncaria tomentosa is a vine commonly known as cat's claw or 'uña de gato' (UG) and is used in traditional Peruvian medicine for the treatment of a wide range of health problems, particularly digestive complaints and arthritis. PURPOSE: The aim of this study was to determine the proposed anti-inflammatory properties of cat's claw. Specifically: (i) does a bark extract of cat's claw protect against oxidant-induced stress in vitro, and (ii) to determine if UG modifies transcriptionally regulated events. METHODS: Cell death was determined in two cell lines, RAW 264.7 and HT29 in response to peroxynitrite (PN, 300 microM). Gene expression of inducible nitric oxide synthase (iNOS) in HT29 cells, direct effects on nitric oxide and peroxynitrite levels, and activation of NF-kappaB in RAW 264.7 cells as influenced by UG were assessed. Chronic intestinal inflammation was induced in rats with indomethacin (7.5 mg/kg), with UG administered orally in the drinking water (5 mg/mL). RESULTS: The administration of UG (100 microg/mL) attenuated (P < 0.05) peroxynitrite-induced apoptosis in HT29 (epithelial) and RAW 264.7 cells (macrophage). Cat's claw inhibited lipopolysaccharide-induced iNOS gene expression, nitrite formation, cell death and inhibited the activation of NF-kappaB. Cat's claw markedly attenuated indomethacin-enteritis as evident by reduced myeloperoxidase activity, morphometric damage and liver metallothionein expression. CONCLUSIONS: Cat's claw protects cells against oxidative stress and negated the activation of NF-kappaB. These studies provide a mechanistic evidence for the widely held belief that cat's claw is an effective anti-inflammatory agent.

Animals↗
PubMed2002

Review article: faecal markers in the assessment of activity in inflammatory bowel disease.

The fundamental pathological process behind ulcerative colitis and Crohn's disease is intestinal inflammation. As the precise cause of this is not yet completely understood, current treatment strategies are aimed at reducing or eliminating the inflammation. Endoscopic examination and histological analysis of biopsy specimens remain the 'gold standard' methods for detecting and quantifying bowel inflammation; however, these techniques are costly, invasive, and repeated examinations are unpopular with patients. Disease activity questionnaires and laboratory 'inflammatory markers', although widely used, show an unreliable correlation with endoscopy and histology. New markers need to be developed to detect and quantify bowel inflammation. These would be of use diagnostically and also an aid to pharmacological treatment.

Biomarkers↗
PubMed2001

Inhibition of nitric oxide synthesis by aminoguanidine increases intestinal damage in the acute phase of rat TNB-colitis.

The role of nitric oxide (NO) in the pathophysiology of inflammatory bowel diseases (IBD) is controversially discussed. The aim of the present study was to investigate the role of NO inhibition in the acute phase of rat 2,4,6-trinitrobenzenesulphonic acid (TNB)-colitis. To inhibit NO synthesis we used aminoguanidine (AG) as a selective inhibitor of inducible nitric oxide synthase (iNOS). TNB-colitis was induced in rats with and without pretreatment with AG (200 mg kg-1 body weight in the drinking water). The severity of colitis was observed over a period of 7 days. On days 1 and 2, AG reduced concentrations of plasma nitrate and nitrite as well as of portal 6-keto-prostaglandin 1alpha. AG pretreatment increased colonic damage and inflammatory response, assessed by colonic myeloperoxidase and serum lactate dehydrogenase activity, macroscopic damage score, tumour necrosis factor-alpha concentration in stool and colonic glutathione content. The AG-treated group showed a higher and prolonged nuclear factor kappaB (NF-kappaB)/Rel binding activity in the colon. We conclude that NOS inhibition by AG is not beneficial in acute intestinal inflammation. With regard to appropriate therapeutic strategies, NF-kappaB/Rel activation might be a more suitable target.

Acute Disease↗
PubMed2001

Effect of 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced ileitis on the motor function of non-inflamed rat gastric fundus.

During intestinal inflammation, motility disturbances are not restricted to inflamed regions, but may also occur in remote non-inflamed sites of the gastrointestinal tract. Our aim was to investigate the motor function of the gastric fundus after the induction of terminal ileitis in the rat. Ileal inflammation was induced by intraluminal installation of 2,4,6-trinitrobenzenesulphonic acid (TNBS) into the ileum. Inflammation was assessed both histologically and biochemically. Contractions and relaxations of longitudinal muscle strips from the gastric fundus were studied 36 h and 1 week later. During the acute phase of ileal inflammation (36 h), the non-inflamed stomach was distended. The contractility of longitudinal muscle strips of the gastric fundus was decreased due to a post-receptor defect. In addition, nonadrenergic noncholinergic (NANC) relaxations were inhibited due to neuronal dysfunction. Aortic contractility remained normal and the mere presence of food in the stomach did not account for the disturbed neuromuscular function in the gastric fundus. Ablation of extrinsic primary afferent neurones by capsaicin further impaired gastric fundus contractility. Transection and re-anastomosis of the jejunum reversed the effect of TNBS-induced ileitis on the neuromuscular function of the gastric fundus. One week after TNBS, cholinergic neurotransmission was increased in the gastric fundus. During acute ileitis, smooth muscle cell contractility and inhibitory NANC neurotransmission are inhibited in the non-inflamed gastric fundus. This phenomenon may be mediated by intrinsic connections within the enteric nervous system.

Animals↗
PubMed2003

Evidence for the critical role of interleukin-12 but not interferon-gamma in the pathogenesis of experimental colitis in mice.

BACKGROUND AND AIMS: The imbalance between helper T (Th)1/Th2 cytokines has been observed in human inflammatory bowel disease and various animal models. Because interleukin (IL)-12 and interferon-gamma (IFN-gamma) productions are known to be a hallmark of Th1-dominant intestinal inflammation such as 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, we strictly addressed the roles of IFN-gamma and IL-12 in the development of colitis, employing knockout mice with IFN-gamma receptor (IFN-gammaR) or IL-12 p40 gene disruptions and mice administered with neutralizing monoclonal antibodies (mAbs) against IFN-gamma or IL-12. METHODS: To induce colitis, 2.5 mg of the hapten reagent TNBS in 50% ethanol was administered into the colon. Two milligrams of rat anti-mouse IFN-gamma mAb, rat anti-mouse IL-12 mAb, or control rat IgG were administered intraperitoneally into mice before TNBS administration. Change in the body weight of mice was evaluated and the degree of inflammation of the colon of these mice was investigated histologically. Immunohistochemical and immunofluorescence analyses were performed to detect CD4+ T cells, macrophages and IL-12 in TNBS-induced colitis lesions. The profile of Th1 and Th2 cytokine expressions in colonic tissues was examined by cytokine-specific semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Single rectal administration of TNBS developed significant colitis in IFN-R-/- mice and anti-IFN-gamma mAb-pretreated mice, as well as control wild-type mice. Conversely, administration of TNBS produced no signs of colitis in IL-12 p40-/- and anti-IL-12 mAb-pretreated mice. CONCLUSIONS: IL-12, but not IFN-gamma, plays a pivotal role in the pathogenesis of TNBS-induced colitis.

Animals↗