Inflammatory Bowel Disease Mucosa Research Articles

Calcineurin inhibition by polaprezinc in rats with experimentally-induced colitis

Aims We investigated the therapeutic effect of polaprezinc (PZ), N-(3-aminopropionyl)- l-histidinato zinc, in rats with experimentally-induced colitis by focusing on calcineurin (CN) inhibition. CN plays a crucial role in T-cell activation and cytokine gene expression and is targeted by immunosuppressants such as cyclosporine and FK506. Main methods Colitis was induced into male Wistar rats by trinitrobenzene sulfonic acid and was treated with intrarectally administered PZ. The inflammation was assessed by the macroscopic damage score, colon wet weight, and proinflammatory mediator expression by RT-PCR analysis. Protein expression of calcineurin and the activation of its substrate, the nuclear factor of activated T cells (NFAT) transcription factor, were also studied. Calcineurin inhibition by PZ was investigated in in vitro experiments using colonic mucosa, purified calcineurin enzyme, and Jurkat T cells. Key findings CN was activated in the colitic mucosa; PZ treatment inhibited CN activation, the expression of proinflammatory cytokines in the mucosa, and thereby ameliorated the experimental colitis in rats. In in vitro experiments, PZ inhibited CN activity, NFAT activation, interleukin-2 expression, and the growth of Jurkat T cells. In the effective concentrations, PZ did not affect cell viability. Significance Our results suggest that PZ can be used as an immunosuppressive agent for the treatment of colitis through its inhibitory effect on CN activity.

DNA methylation of colon mucosa in ulcerative colitis patients: Correlation with inflammatory status

Although DNA methylation of colonic mucosa in ulcerative colitis (UC) has been suggested, the majority of published reports indicate the correlation between methylation of colon mucosa and occurrence of UC-related dysplasia or cancer without considering the mucosal inflammatory status. The aim of this study was to verify whether mucosal inflammation-specific DNA methylation occurs in the colon of UC. Of 15 gene loci initially screened, six loci (ABCB1, CDH1, ESR1, GDNF, HPP1, and MYOD1) methylated in colon mucosa of UC were analyzed according to inflammatory status using samples from 28 surgically resected UC patients. Four of six regions (CDH1, GDNF, HPP1, and MYOD1) were more highly methylated in the active inflamed mucosa than in the quiescent mucosa in each UC patient (P = 0.003, 0.0002, 0.02, and 0.048, respectively). In addition, when the methylation status of all samples taken from examined patients was stratified according to inflammatory status, methylation of CDH1 and GDNF loci was significantly higher in active inflamed mucosa than in quiescent mucosa (P = 0.045 and 0.002, respectively). Multiple linear regression analysis revealed that active inflammation was an independent factor of methylation for CDH1 and GDNF. DNA methyltransferase 1 and 3b were highly expressed in colon epithelial cells with active mucosal inflammation, suggesting their involvement in inflammation-dependent methylation. Methylation in colonic mucosa of UC was correlated with mucosal inflammatory status, suggesting the involvement of methylation due to chronic active inflammation in UC carcinogenesis.

TH1 and TH17 interactions in untreated inflamed mucosa of inflammatory bowel disease, and their potential to mediate the inflammation.

TH1 and TH17 interactions in untreated inflamed mucosa of inflammatory bowel disease, and their potential to mediate the inflammation.

Activated Syndecan-1 Shedding Contributes to Mice Colitis Induced by Dextran Sulfate Sodium

Syndecan-1(Sdc1) plays important roles in many steps of inflammatory responses. In ulcerative colitis patients, decreased Sdc1 expression was observed and Sdc1 analogue heparin could improve the disease course. A better understanding of how Sdc1 functions in colitis will benefit the disease intervention. To evaluate the role of Sdc1 in dextran sulfate sodium (DSS)-induced colitis. BALB/c mice were grouped randomly into control, DSS, and heparin+DSS. The DSS group was given 4% DSS orally and heparin+DSS group was given 4% DSS with heparin (enoxaparin) subcutaneously, while the control was given distilled water orally. All mice were killed at day 7. Disease activities, histopathological changes, membrane-bound and free Sdc1 level and mRNA expression of Sdc1, IL-1, and IL-10 in colon mucosa were detected. Significant colitis was observed in the DSS group, but disease activity index and histological score showed significant lower in the heparin+DSS group than those in the DSS group. Compared to the control group, decreased Sdc1 protein expression was detected in colon mucosa of DSS-induced colitis while Sdc1 ectodomain level in serum was much higher. Inhibited Sdc1 ectodomain shedding was detected in the heparin+DSS group compared to the DSS group. RT-PCR demonstrated that both IL-1 and IL-10 expression were up-regulated in DSS-induced colitis while heparin lessened the up-regulation extent. Sdc1 shedding is activated in DSS-induced colitis and heparin, which mimics Sdc1 functions, relieves colitis severity by inhibiting Sdc1 shedding and down-regulating cytokines expression.

Apoptosis and inflammation: role of adipokines in inflammatory bowel disease.

OBJECTIVES:Leptin and adiponectin (APN) are adipokines produced by adipocytes that participate in the modulation of immune and inflammatory responses. In Crohn's disease (CD), fat wrapping surrounding the inflamed intestine produces high levels of leptin and APN. In inflammatory bowel disease (IBD), apoptosis resistance of lamina propria T lymphocytes (LPL-T) is one of the mechanisms that maintains chronic inflammation. We addressed the mechanism by which leptin and APN regulate inflammation and apoptosis in IBD.METHODS:Immune cell infiltration, several factors expressed by adipose tissue (AT), and spontaneous release of cytokines by adipocytes were measured. The presence of APN and leptin in intestinal mucosa was detected and their effect on LPL-T apoptosis, signal transducer and activator of transcription 3 (STAT3), Suppressor of Cytokine Signaling 3 (SOCS3), Bcl-2 and Bcl-xL expression, and cytokine production was studied. In addition, the effects of globular and high-molecular-weight (HMW) APN on LPL-T cytokine production and apoptosis were studied.RESULTS:Higher levels of several chemokines, cytokines, and growth factors were present in AT near active than near inactive disease. A significantly higher amount of inflammatory infiltrate was present in AT near active CD than near ulcerative colitis, controls, and near the inactive area of CD. There were no changes in the ratios of APN molecular weight in control and IBD adipocyte products. Leptin and APN inhibited anti-CD3-stimulated-LPL-T apoptosis and potentiated STAT3 phosphorylation, Bcl-2, and Bcl-xL expression in IBD and control mucosa. However, SOCS3 expression was suppressed only in IBD. Both globular and HMW APN have similar effects on LPL-T cytokine production and apoptosis. Leptin and APN enhanced interleukin (IL)-10 production by anti-CD3-stimulated LPL-T in IBD only. APN, but not leptin, increased anti-CD3-induced IL-6 levels in LPL-T only in IBD patients. IL-10 exerts its anti-inflammatory activity in the presence of SOCS3 suppression by leptin or APN.CONCLUSION:Leptin and APN maintain the inhibition of anti-CD3-stimulated LPL-T apoptosis by enhancing Bcl-2 and Bcl-xL overexpression and promoting STAT3 phosphorylation while suppressing SOCS3.

Down-regulation of single immunoglobulin interleukin-1R-related molecule (SIGIRR)/TIR8 expression in intestinal epithelial cells during inflammation

Single immunoglobulin (Ig) interleukin-1R-related molecule (SIGIRR) is an Ig-like membrane protein critical for negative regulation of Toll-like receptor (TLR)-4-mediated signalling. We investigated SIGIRR expression and its regulation mechanism in intestinal epithelial cells (IECs) during inflammation. Endoscopic biopsy specimens were obtained from active and inactive colonic mucosa of ulcerative colitis (UC) patients, then SIGIRR expression was examined using real-time polymerase chain reaction (PCR) and immunohistochemistry (IH). Mice experimental colitis models were established by administrations of sulphonic acid (TNBS) and dextran sodium sulphate (DSS), and epithelial expression of SIGIRR was examined using real-time PCR, IH and flow cytometry. The effects of lipopolysaccharide (LPS) and tumour necrosis factor (TNF)-α on SIGIRR expression were evaluated in vitro using cultured IECs. To elucidate SIGIRR expression regulation in IECs, binding ability of the transcription factor SP1 at the responsive element of the SIGIRR promoter was examined using gel-shift and chromatin immunoprecipitation (ChIP) assays. In human colonic samples, SIGIRR was expressed mainly in IECs at levels significantly higher in inactive compared to active mucosa. In the mice, SIGIRR colonic expression decreased rapidly after colitis development and returned gradually to basal levels. Experimental colitis-mediated down-regulation of SIGIRR in IECs was also confirmed by IH and flow cytometry results. Further, inflammatory conditions induced by TLR ligands and TNF-α caused significant down-regulation of SIGIRR expression in IECs, which was dependent upon decreased SP1 binding at the responsive element of the SIGIRR promoter. We found that SIGIRR is expressed in IECs and serves as a negative regulator to maintain gut innate immunity, which is down-regulated during inflammation by inhibition of an SP1-mediated pathway.

Immunohistochemical expression of CDX2, β-catenin, and TP53 in inflammatory bowel disease-associated colorectal cancer

Inflammatory bowel disease (IBD) exposes patients to an increased risk of colorectal cancer (i-CRC) and differences between i-CRC and sporadic colorectal cancer (s-CRC) pathogenesis were reported. In s-CRC, studies indicate abnormalities in the tumor-suppressor gene Cdx2. This study compared CDX2, β-catenin, and TP53 expression in i-CRC, s-CRC, noncancer IBD, and normal control colonic mucosa. Expression was investigated by immunohistochemistry in 10 normal, 20 s-CRC, 11 noncancer colonic IBD and 30 i-CRC samples, and in four samples of Crohn's disease (CD)-associated small bowel adenocarcinoma (i-SBA). In normal and noncancer IBD samples, CDX2 was confined to the colonocytes nuclei. CDX2 expression was normal in 90% of i-CRC, regardless of tumor differentiation or inflammation intensity. By contrast, CDX2 expression was altered in 45% s-CRC, particularly at the front of invasion in undifferentiated tumors. β-Catenin was restricted to cell membrane in all controls, in 91% noncancer IBD, and in 84% i-CRC samples, whereas 35% s-CRC showed cytoplasmic redistribution and exclusive nuclear staining at the front of invasion. TP53 was strongly and homogeneously expressed in i-CRC nuclei compared to normal control or s-CRC, and increases with inflammation intensity. Nested or diffuse TP53 was found in 81.8% of noncancer IBD samples with a higher proportion of TP53-expressing cells in the most inflamed samples. CDX2, β-catenin, and TP53 expression in CD-associated SBA appears similar to that of i-CRC. Neither Cdx2 nor β-catenin alterations are prominent features of i-CRC. In i-CRC and CD-associated SBA, carcinogenesis is associated early with p53 mutations and to inflammation intensity.

Expression of intestinal MUC17 membrane-bound mucin in inflammatory and neoplastic diseases of the colon

AimTo determine the cellular location and expression of MUC17 mucin in specimens of normal, inflamed and neoplastic colon.MethodsImmunohistochemical analysis of human surgical resection specimens (n=106) was performed with a specific...

Mucolytic Bacteria With Increased Prevalence in IBD Mucosa Augment In Vitro Utilization of Mucin by Other Bacteria

Mucosa-associated bacteria are increased in inflammatory bowel disease (IBD), which suggests the possibility of an increased source of digestible endogenous mucus substrate. We hypothesized that mucolytic bacteria are increased in IBD, providing increased substrate to sustain nonmucolytic mucosa-associated bacteria. Mucolytic bacteria were characterized by the ability to degrade human secretory mucin (MUC2) in pure and mixed anaerobic cultures. Real-time PCR was used to enumerate mucosa-associated mucolytic bacteria in 46 IBD and 20 control patients. Bacterial mucolytic activity was tested in vitro using purified human MUC2. We confirm increased total mucosa-associated bacteria 16S rRNA gene in macroscopically and histologically normal intestinal epithelium of both Crohn's disease (CD) (mean 1.9-fold) and ulcerative colitis (UC) (mean 1.3-fold). We found a disproportionate increase in some mucolytic bacteria. Mean Ruminococcus gnavus were increased >4-fold and Ruminococcus torques ∼100-fold in macroscopically and histologically normal intestinal epithelium of both CD and UC. The most abundantly detected mucolytic bacterium in controls, Akkermansia muciniphila, was reduced many fold in CD and in UC. Coculture of A. muciniphila with MUC2 as the sole carbon source led to reduction in its abundance while it augmented growth of other bacteria. Mucolytic bacteria are present in healthy humans, where they are an integral part of the mucosa-associated bacterial consortium. The disproportionate increase in R. gnavus and R. torques could explain increased total mucosa-associated bacteria in IBD.

Peroxisome proliferator‐activated receptor γ 2 mutation may cause a subset of ulcerative colitis

Previous studies suggest the homeostasis between acquisition of tolerance to the indigenous microflora and protective immune responses appears to be disrupted in inflammatory bowel disease (IBD). Some experimental studies indicate peroxisome proliferator-activated receptor γ (PPARγ) has been implicated as a regulator of intestinal inflammatory responses. In addition, the toll-like receptor (TLR)-4 can regulate expression of PPARγ in colonic epithelial cells. We attempted to demonstrate whether the functional imbalance between TLRs and PPARγ could lead to the onset and some polymorphisms of those genes could contribute to susceptibility to IBD. RT-PCR analysis were performed to detect TLR4 and PPARγ mRNA associated with those of P65 of NFκB, TNFα, MyD88, NOD2/CARD15, TLR-2,5,9, in the diseased colonic mucosa in ulcerative colitis (UC; n = 13) and Crohn's disease (CD; n = 7) compared with normal controls (n = 18). Consequently, we genotyped UC (n = 29) and CD (n = 10) compared with normal controls (n = 134) for the prevalence of suspicious mutations. In a subset of UC patients who were revealed to carry PPARγ Pro12Ala mutation later, impaired expression of normal PPARγ mRNA was noted in the diseased mucosa accompanied with upregulations of MyD88 TLR-4, 5, 9, P65 and TNFα in mRNA levels. The prevalence of PPARγ Pro12Ala mutation was more frequently found in UC patients compared with CD patients and normal controls (P < 0.05). These findings suggested that imbalances between TLRs and PPARγ in response to luminal bacteria could lead to colonic inflammation in some UC patients. Alternative explanations will be needed for the onset of the rest of UC and CD.

M1790 IL-27 is Highly Expressed in Inflamed Mucosa of Inflammatory Bowel Disease and Downregulates TH17 Cell Differentiation

M1790 IL-27 is Highly Expressed in Inflamed Mucosa of Inflammatory Bowel Disease and Downregulates TH17 Cell Differentiation

505 Epigenetic Regulation of Inflammation-Induced Endothelial-to-Mesenchymal Transition (EndoMT): A Novel Mechanism of Fibrosis in Inflammatory Bowel Disease (IBD)

BACKGROUND: Intestinal fibrosis is a common and potentially serious complication of inflammatory bowel disease (IBD). In addition to mesenchymal cells, endothelial cells can contribute to fibrosis through the recently described process of EndoMT. We investigated whether i) human intestinal microvascular endothelial cells (HIMEC) can undergo EndoMT and contribute to fibrosis in IBD, and ii) epigenetic changes are involved in mediation of EndoMT.MATERIALS ANDMETHODS: HIMEC exposed to TGF-β1, IL-1β and TNF-α or supernatants of lamina propria mononuclear cells (LPMC) were evaluated for morphological, phenotypic and functional changes compatible with EndoMT. Microarray genomic analysis was used to identify transcription factors controlling the transformation process. Evidence of in situ and In Vivo EndoMT was sought in human and experimental IBD tissues. Chromatin immunoprecipitation (ChIP) assays were performed to identify specific histone modification changes on the promoters of von Willebrand factor (vWF) and collagen1 alpha2 (Col1α2) genes (markers of endothelial cells and fibroblasts, respectively) during EndoMT. RESULTS: The combination of TGF-β1, IL-1β and TNF-α induced morphologic and phenotypic changes in HIMEC consistent with EndoMT, and these were reproduced using supernatants of activated LPMC. Transformed HIMEC exhibited loss of acetylated LDL-uptake, enhanced extracellular matrix secretion, and acquisition of de novo collagen synthesis capacity. These functional alterations persisted at 10 days after removal of the inducing agents, and then still were associated with an approximate 8-fold upregulation of Col1α2 gene expression and 1.6-fold downregulation of vWF gene expression. EndoMT was detected in inflamed microvessels of human IBD mucosa and TNBS-induced colonic fibrosis of Tie2-GFP reporter mice. Genomic analysis uncovered Sp1 as the dominant transcriptional regulator of EndoMT. Finally, ChIP analysis revealed increased methylation of lysines 9 and 27 in histone H3 associated with repression of vWF gene expression, while increased acetylation of histone H4 accompanied activation of Col1α2 gene expression. CONCLUSIONS: Inflammatory stimuli induce trans-differentiation of mucosal microvascular cells into mesenchymal cells In Vitro and In Vivo, supporting the notion that the microvasculature undergoes EndoMT in IBD and contributes to fibrogenesis. These events involve epigenetic changes such as histone modifications crucial to regulation of EndoMT, and define unique pro-fibrotic epigenotypes that could become targets of selective anti-fibrotic therapies in IBD.

Similarity in the metabolic profile in macroscopically involved and un-involved colonic mucosa in patients with inflammatory bowel disease: an in vitro proton ( 1H) MR spectroscopy study

Background The histological extent of inflammatory bowel disease (IBD) is greater than that evident by colonoscopic evaluation. We hypothesized that metabolic profile in macroscopically un-involved colonic mucosa in IBD is similar to that of controls with healthy colon. We thus assessed the differences in metabolic profile in macroscopically involved and un-involved colonic mucosa of IBD patients to further substantiate the extent of disease. Patients and Methods Colonic mucosal biopsies were obtained and snap frozen from both the macroscopically un-involved and involved colonic mucosa of IBD patients and macroscopically normal colonic mucosa of controls and were subjected to in-vitro high-resolution proton ( 1H) magnetic resonance (MR) spectroscopy and the concentrations of metabolites were determined. Results Thirty-two metabolites were assigned in the proton MR spectrum of colonic mucosa of IBD patients. The concentrations of amino acids (isoleucine, leucine, valine, arginine, lysine, glutamine/glutamate, alanine), membrane metabolites (choline, glycerophosphorylcholine/phosphorylcholine), glycolytic product (lactate) and short chain fatty acid (formate) were significantly lower while significantly high level of glucose were observed in the macroscopically un-involved colonic mucosa of IBD patients compared to the macroscopically normal mucosa of controls. There was no significant difference in the concentrations of metabolites in macroscopically involved and un-involved colonic mucosa of IBD patients. Conclusions The metabolic profile in macroscopically un-involved colonic mucosa of IBD patients is similar to that of macroscopically involved mucosa but different from colonic mucosa of controls. This suggests that even macroscopically un-involved colonic mucosa is metabolically abnormal and may explain the increase in extent of disease with time.

Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis

Interleukin (IL)-33 is a cytokine belonging to the IL-1 family. IL-33 has been shown to elicit a Th2-like cytokine response in immune cells. In this study, we investigated IL-33 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-33 expression in human colonic subepithelial myofibroblasts (SEMFs). IL-33 mRNA expression was determined by real-time polymerase chain reaction (PCR). IL-33 expression in the IBD mucosa was evaluated by immunohistochemical methods. IL-33 mRNA expression was significantly elevated in active lesions from patients with ulcerative colitis (UC), but was not detected in inactive lesions from UC patients or in lesions from patients with either active or inactive Crohn's disease. Colonic SEMFs were identified as a major source of IL-33 in the mucosa. IL-1β and tumor necrosis factor-α (TNF-α) significantly enhanced IL-33 mRNA and protein expression in isolated colonic SEMFs. IL-1β and TNF-α did not affect IL-33 expression in intestinal epithelial cell lines (HT-29 and Caco-2 cells). This IL-1β- and TNF-α-induced IL-33 mRNA expression was mediated by p42/44 mitogen activated protein kinase (MAPK) pathway-dependent activation of nuclear factor (NF)-κB and activator protein (AP)-1. IL-33, derived from colonic SEMFs, may play an important role in the pathophysiology of UC.

Involvement of the IL-22/REG Iα axis in ulcerative colitis

The Regenerating gene (REG) Iα protein, a trophic and/or anti-apoptotic factor, is important in the pathophysiology of gastrointestinal inflammation. Interleukin (IL)-22 is a recently identified cytokine that is suggested to have pivotal roles in inflammatory bowel diseases. We therefore investigated the involvement of the IL-22/REG Iα axis and examined the mechanism of regulation of REG Iα expression by IL-22 stimulation in ulcerative colitis (UC) mucosa. Expression of IL-22, IL-22 receptor 1 (IL-22R1), and REG Iα in UC mucosa was analyzed by real-time RT-PCR and immunohistochemistry. The effects of IL-22 on REG Iα protein expression were examined using a small-interfering RNA for STAT3, an MAPK inhibitor or a PI3K inhibitor. The element responsible for IL-22-induced REG Iα promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay. The expression of IL-22 was enhanced in infiltrating inflammatory cells, and that of IL-22R1 and REG Iα was concurrently enhanced in the inflamed epithelium in UC mucosa. The levels of REG Iα and IL-22 mRNA expression were strongly correlated, and the distributions of REG Iα- and IL-22R1-positive epithelial cells were very similar. IL-22 simulation enhanced the expression of REG Iα protein through STAT3 tyrosine phosphorylation in colon cancer cells. The IL-22-responsive element was located between −142 and −134 in the REG Iα promoter region. REG Iα protein may have a pathophysiological role as a biological mediator for immune cell-derived IL-22 in the UC mucosa.

AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

The AGA Institute Medical Position Panel consisted of the authors of the technical review, a community-based gastroenterologist (Robert P. McCabe, MD, Minnesota Gastroenterology), academic-based gastroenterologists (Themistocles Dassopoulos, MD, James D. Lewis, MD, and Thomas A. Ullman, MD), an insurance provider representative (Tom James III, MD Physician Advisor, Strategic Advisory Group, Humana), a colon and rectal surgeon (Robin McLeod, MD, Mount Sinai Hospital-Canada), a pathologist (Lawrence J. Burgart, MD, Minnesota Gastroenterology), chair of the AGA Institute Clinical Practice and Quality Management Committee (John Allen, MD, Minnesota Gastroenterology), and chair of the Practice Management and Economics Committee (Joel V. Brill, MD, Predictive Health, LLC) .

Plasma histamine levels (H) during adjunctive H1-receptor antagonist treatment with loratadine in patients with active Inflammatory Bowel disease (IBD)

Histamine exerts a broad range of both proinflammatory and immunoregulatory effects in the body. Although there are somewhat controversial findings about the role of mast cells in Inflammatory Bowel Disease (IBD), recent immunologic findings suggest that mast cells, histamine and other immunomediators associated with a TH2-cell response may play a role in ulcerative colitis and in early lesions of Crohn’s disease, both chronic inflammatory disorders of the large bowel [1, 2], leading to bloody diarrhoea, anaemia, abdominal pain and weight loss. Tissue histamine content and mast cell secretion have been reported to be increased in affected mucosa and active flares of IBD [2–4], while urinary methylhistamine excretion was found to be low during remission [5]. Therefore, we performed an adjunctive antihistamine trial in IBD and explored plasma histamine levels during standard treatment with or without loratadine.

The increased mucosal mRNA expressions of complement C3 and interleukin-17 in inflammatory bowel disease

Recent studies have demonstrated that the complement system participates in the regulation of T cell functions. To address the local biosynthesis of complement components in inflammatory bowel disease (IBD) mucosa, we investigated C3 and interleukin (IL)-17 mRNA expression in mucosal samples obtained from patients with IBD. The molecular mechanisms underlying C3 induction were investigated in human colonic subepithelial myofibroblasts (SEMFs). IL-17 and C3 mRNA expressions in the IBD mucosa were evaluated by real-time polymerase chain reaction. The C3 levels in the supernatant were determined by enzyme-linked immunosorbent assay. IL-17 and C3 mRNA expressions were elevated significantly in the active lesions from ulcerative colitis (UC) and Crohn's disease (CD) patients. There was a significant positive correlation between IL-17 and C3 mRNA expression in the IBD mucosa. IL-17 stimulated a dose- and time-dependent increase in C3 mRNA expression and C3 secretion in colonic SEMFs. The C3 molecules secreted by colonic SEMFs were a 115-kDa alpha-chain linked to a 70-kDa beta-chain by disulphide bonds, which was identical to serum C3. The IL-17-induced C3 mRNA expression was blocked by p42/44 mitogen-activated protein kinase (MAPK) inhibitors (PD98059 and U0216) and a p38 MAPK inhibitor (SB203580). Furthermore, IL-17-induced C3 mRNA expression was inhibited by an adenovirus containing a stable mutant form of I kappaB alpha. C3 and IL-17 mRNA expressions are enhanced, with a strong correlation, in the inflamed mucosa of IBD patients. Part of these clinical findings was considered to be mediated by the colonic SEMF response to IL-17.

Limitations in assessment of mucosal healing in inflammatory bowel disease.

An emerging parameter to define the effectiveness of new therapeutic agents in clinical trials, and by extension, for use in day-to-day clinical practice has been labeled mucosal healing. It has been hypothesized that complete healing of the intestinal mucosa in inflammatory bowel diseases should result in reduced disease complications, reduced hospitalization and reduced surgical treatment. By implication, the natural history of inflammatory bowel disease might then be altered. Measurement of mucosal healing, however, is largely observational, requiring repeated invasive endoscopic examinations, sometimes with mucosal biopsies. Other indirect imaging methods may play a role in this assessment along with other surrogate markers, including intestinal permeability. These measurements may have significant limitations that prohibit precise correlation with symptom-based disease activity indices in clinical trials. This likely reflects the dynamic nature of this evolving and individualized inflammatory process that tends to be focused, but not limited, to the mucosa of the intestinal tract.

Neuroinflammation in inflammatory bowel disease

Inflammatory bowel disease is a chronic intestinal inflammatory condition, the pathology of which is incompletely understood. Gut inflammation causes significant changes in neurally controlled gut functions including cramping, abdominal pain, fecal urgency, and explosive diarrhea. These symptoms are caused, at least in part, by prolonged hyperexcitability of enteric neurons that can occur following the resolution of colitis. Mast, enterochromaffin and other immune cells are increased in the colonic mucosa in inflammatory bowel disease and signal the presence of inflammation to the enteric nervous system. Inflammatory mediators include 5-hydroxytryptamine and cytokines, as well as reactive oxygen species and the production of oxidative stress. This review will discuss the effects of inflammation on enteric neural activity and potential therapeutic strategies that target neuroinflammation in the enteric nervous system.