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PubMed2004

TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice.

In previous studies, we have shown that murine CD4+CD25+ regulatory T cells produce high levels of TGF-beta1 in a cell surface and/or secreted form, and blockade of such TGF-beta1 by anti-TGF-beta curtails the ability of these cells to suppress CD25- T cell proliferation and B cell Ig production in in vitro suppressor assays. In further support for the role of TGF-beta1 in suppression by CD4+CD25+ T cells, we show in this study that another TGF-beta1-blocking molecule, recombinant latency-associated peptide of TGF-beta1 (rLAP), also reverses suppression by mouse CD4+CD25+ T cells as well as their human counterparts, CD4+CD25(high) T cells. In addition, we show that CD25- T cells exposed to CD4+CD25+ T cells in vitro manifest activation of Smad-2 and induction of CD103, the latter a TGF-beta-inducible surface integrin. In further studies, we show that while CD4+CD25+ T cells from TGF-beta1-deficient mice can suppress CD25- T cell proliferation in vitro, these cells do not protect recipient mice from colitis in the SCID transfer model in vivo, and, in addition, CD4+LAP+, but not CD4+LAP- T cells from normal mice protect recipient mice from colitis in this model. Together, these studies demonstrate that TGF-beta1 produced by CD4+CD25+ T cells is involved in the suppressor activity of these cells, particularly in their ability to regulate intestinal inflammation.

Adoptive Transfer↗
PubMed2006

Corticotropin-releasing hormone receptor 2-deficient mice have reduced intestinal inflammatory responses.

Corticotropin-releasing hormone (CRH) and urocortins (Ucn) bind with various affinities to two G-protein-coupled receptors, CRHR1 and CRHR2, which are expressed in brain and in peripheral tissues, including immune cells. CRHR2-deficient mice display anxiety-like behavior, hypersensitivity to stress, altered feeding behavior and metabolism, and cardiovascular abnormalities. However, the phenotype of these mice in inflammatory responses has not been determined. In the present study we found that compared with wild-type CRHR2-null mice developed substantially reduced intestinal inflammation and had lower intestinal mRNA expression of the potent chemoattractants keratinocyte chemokine and monocyte chemoattractant protein 1 following intraluminal exposure to Clostridium difficile toxin A, a potent enterotoxin that mediates antibiotic-associated diarrhea and colitis in humans. This effect was recapitulated by administration of astressin 2B, a selective CRHR2 antagonist, before toxin A exposure. Moreover, Ab array analysis revealed reduced expression of several inflammatory chemokines, including keratinocyte chemokine and monocyte chemoattractant protein 1 in toxin A-exposed mice pretreated with astressin 2B. Real-time RT-PCR of wild-type mouse intestine showed that only UcnII, but not other Ucn, was significantly up-regulated by ileal administration of toxin A at 4 h compared with buffer exposure. We also found that human colonic epithelial HT-29 cells express CRHR2alpha mRNA, whereas expression of beta and gamma spliced variants was minimal. Moreover, treatment of HT-29 cells with UcnII, which binds exclusively to CRHR2, stimulated expression of IL-8 and monocyte chemoattractant protein 1. Taken together, these results provide direct evidence that CRHR2 mediates intestinal inflammatory responses via release of proinflammatory mediators at the colonocyte level.

Animals↗
PubMed1999

Neurotensin is a proinflammatory neuropeptide in colonic inflammation.

The neuropeptide neurotensin mediates several intestinal functions, including chloride secretion, motility, and cellular growth. However, whether this peptide participates in intestinal inflammation is not known. Toxin A, an enterotoxin from Clostridium difficile, mediates pseudomembranous colitis in humans. In animal models, toxin A causes an acute inflammatory response characterized by activation of sensory neurons and intestinal nerves and immune cells of the lamina propria. Here we show that neurotensin and its receptor are elevated in the rat colonic mucosa following toxin A administration. Pretreatment of rats with the neurotensin receptor antagonist SR-48, 692 inhibits toxin A-induced changes in colonic secretion, mucosal permeability, and histologic damage. Exposure of colonic explants to toxin A or neurotensin causes mast cell degranulation, which is inhibited by SR-48,692. Because substance P was previously shown to mediate mast cell activation, we examined whether substance P is involved in neurotensin-induced mast cell degranulation. Our results show that neurotensin-induced mast cell degranulation in colonic explants is inhibited by the substance P (neurokinin-1) receptor antagonist CP-96,345, indicating that colonic mast activation in response to neurotensin involves release of substance P. We conclude that neurotensin plays a key role in the pathogenesis of C. difficile-induced colonic inflammation and mast cell activation.

Animals↗
PubMed1994

Assessment of inflammatory activity in Crohn's disease.

Complaints or symptoms of Crohn's disease can be due either to intestinal inflammation or to anatomical abnormalities such as strictures, fistulas and previous intestinal resection, or to a combination of these factors. Since anti-inflammatory or immunosuppressive drugs are only effective in reducing inflammation, assessment of the presence or absence of active inflammation is of great clinical importance. Several disease activity indices have been developed, but none is able to accurately assess inflammatory activity in Crohn's disease. Furthermore, blood parameters of inflammation, such as ESR, leukocytes, thrombocytes and albumin, are not bowel-specific. In contrast, faecal inflammatory parameters are specific for intestinal inflammation. Preliminary results from our laboratory suggest that measurement of intestinal alpha 1-antitrypsin clearance is a sensitive and bowel-specific indicator of active inflammation in Crohn's disease. This inexpensive, safe and patient-friendly measurement deserves a prominent place, not only in drug trials but also in clinical management of patients with Crohn's disease.

Biomarkers↗
PubMed2004

Modulating the intestinal immune system: the role of lymphotoxin and GALT organs.

The gut associated immune system fences off potentially harmful intestinal antigens from the systemic circulation and induces systemic tolerance against luminal antigens. Intestinal immune responses against luminal antigens include IgA secretion and induction of regulatory cells. Unlike few other cytokines, lymphotoxin alpha/beta regulates the development of intestinal lymphoid organs. The embryonic development of Peyer's patches, postnatal lamina propria B cell development, and isolated lymphoid follicle development all depend on lymphotoxin beta receptor interactions. Lymphotoxin alpha/beta signalling also contributes to the development of mesenteric lymph nodes. In addition, intestinal inflammation is suppressed by inhibition of lymphotoxin beta signalling, an observation which has initiated clinical studies using this treatment principal. Intestinal follicular lymphoid organs are sites of antigen presentation. Antigen presenting cells tune the delicate balance between intestinal immune tolerance and inflammation. Therefore, gut associated lymphatic organs and factors regulating their development are critical for the prevention of adverse immune reactions to intestinal antigens. This review provides an overview on the role of lymphotoxin and the gut associated lymphatic organs in the regulation of oral tolerance and intestinal inflammation.

Animals↗
PubMed2001

B7 interactions with CD28 and CTLA-4 control tolerance or induction of mucosal inflammation in chronic experimental colitis.

CD28-B7 interaction plays a critical costimulatory role in inducing T cell activation, while CTLA-4-B7 interaction provides a negative signal that is essential in immune homeostasis. Transfer of CD45RB(high)CD4(+) T cells from syngeneic mice induces transmural colon inflammation in SCID recipients. This adoptive transfer model was used to investigate the contribution of B7-CD28/CTLA-4 interactions to the control of intestinal inflammation. CD45RB(high)CD4(+) cells from CD28(-/-) mice failed to induce mucosal inflammation in SCID recipients. Administration of anti-B7.1 (but not anti-B7.2) after transfer of wild-type CD45RB(high)CD4(+) cells also prevented wasting disease with colitis, abrogated leukocyte infiltration, and reduced production of proinflammatory cytokines IL-2 and IFN-gamma by lamina propria CD4(+) cells. In contrast, anti-CTLA-4 treatment led to deterioration of disease, to more severe inflammation, and to enhanced production of proinflammatory cytokines. Of note, CD25(+)CD4(+) cells from CD28(-/-) mice similar to those from the wild-type mice were efficient to prevent intestinal mucosal inflammation induced by the wild-type CD45RB(high) cells. The inhibitory functions of these regulatory T cells were effectively blocked by anti-CTLA-4. These data show that the B7-CD28 costimulatory pathway is required for induction of effector T cells and for intestinal mucosal inflammation, while the regulatory T cells function in a CD28-independent way. CTLA-4 signaling plays a key role in maintaining mucosal lymphocyte tolerance, most likely by activating the regulatory T cells.

Abatacept↗
PubMed1986

Intestinal immunity and inflammation: recent progress.

The previous sections illustrate that we are still defining (a) which sets of lymphoid cells are present in the intestine and which are not, (b) which sets are peculiar to the intestine, and (c) how the sets that are there function in the intestinal microenvironment. An understanding of the latter point is going to require knowledge of how these sets communicate with and regulate one another via cell surface molecules such as MHC class I and class II molecules, and via soluble mediators or lymphokines. The recent advances in various technologies make this a particularly exciting time in this field because the tools are now available to address and answer some of these basic and important questions in mucosal immunology. At the same time these advances hold great promise for our eventual understanding of chronic inflammatory diseases of the intestine. As was mentioned at the outset, the immune system has considerable power for both protection and destruction. It remains a puzzle how this latter potential is contained and controlled in the intestine of most individuals, such that they do not have inflammatory disease even in the setting of intense stimulation by substances, such as endotoxin, that are phlogistic elsewhere in the body. An answer to the question of why everyone does not have intestinal inflammation could provide new insights into the mechanisms involved in chronic intestinal inflammatory diseases. The recent advances just detailed, as well as others sure to come, suggest that it is only a matter of time before such questions are answered.

Animals↗
PubMed1998

Localization and secretion of tissue kallikrein in peptidoglycan-induced enterocolitis in Lewis rats.

The plasma kallikrein-kinin system is a mediator of intestinal inflammation induced by peptidoglycan-polysaccharide from group A streptococci (PG-APS) in rats. In this study we investigated the participation of intestinal tissue kallikrein (ITK). Lewis rats were injected intramurally with PG-APS. ITK was visualized by immunohistochemical staining. Cecal ITK concentration was measured by radioimmunoassay, and gene expression was evaluated by RNase protection assay. Kallikrein-binding protein (KBP) was evaluated in plasma by ELISA. Tissue kallikrein was identified in cecal goblet cells in both control and PG-APS-injected rats and in macrophages forming granulomas in inflamed tissues. Cecal ITK was significantly lower in acute and chronic phases of inflammation and in supernatant from in vitro cultures of inflamed cecum. ITK mRNA levels were not significantly different. Plasma KBP levels were significantly reduced in inflamed rats. The presence of tissue kallikrein in macrophages suggests participation in experimental colitis. The decrease of ITK in the inflamed intestine associated with unchanged mRNA levels suggests ITK release during intestinal inflammation.

Animals↗
PubMedDate not supplied

Effect of a synthetic analog of prostaglandin E1 on the intestinal mucosa of methotrexate-treated rats.

Administration of methotrexate to rats sometimes induces small intestinal damage. A synthetic analog of prostaglandin E1, OP-1206 [17S,20-dimethyl-trans-delta2-prostaglandin E1] may possibly provide therapeutic benefits to help recovery from such small intestinal damage. The purpose of this study was to evaluate the effect of OP-1206 on methotrexate-induced small intestinal damage in rats. Methotrexate (15 mg/kg body weight) was orally administered to rats once daily for 5 days. OP-1206 (0.5 microg/kg body weight) was orally administered to rats twice a day for 5 days and on the 6th day the small intestine of the rats were examined histologically and biochemically. The methotrexate treatment of rats caused a severe histological change in the small intestinal mucosa, whereas the treatment combined of OP-1206 with methotrexate showed similar histological features of the small intestinal mucosa as that of the control rats. On the other hand, an acute intestinal inflammation was evaluated by determining myeloperoxidase activity. The myeloperoxidase activity in the small intestinal mucosa of the methotrexate-treated rats increased remarkably, whereas that of the methotrexate and OP-1206-treated rats was significantly lower than that of the methotrexate-treated rats. Thus, it was shown histologically and biochemically that OP-1206 was effective in protecting the small intestine from methotrexate-induced damage.

Alprostadil↗
PubMed1998

The gut. A key metabolic organ protected by lactoferrin during experimental systemic inflammation in mice.

The gastrointestinal tract may be viewed as an ecologic system in which a balance between the host and bacterial flora exists. Two major host components appear to be involved in maintaining this balance. The first is a non-specific structural barrier provided by the epithelial layer of the gastrointestinal mucosae. The second component involves functional immunological elements found in the mucosal and submucosal compartments, e.g., gut associated lymphoid tissue. When gut integrity is disrupted by invasive pathogens or by trauma, a myriad of pro-inflammatory mediators are released from cells in the gut wall that exert actions in the tissue or gut lumen. One of these mediators is lactoferrin, and iron binding protein found in high concentration in most human exocrine secretions. Despite controversies on its physiological role, evidence is emerging that lactoferrin plays an important role in host defense against toxic metabolites and antigenic components of potential pathogens2-4. This manuscript is intended to provide an overview of work related to lactoferrin's modulatory roles in inflammation, and to present observations from experimental studies on the preservation of intestinal structure and function by lactoferrin during intestinal inflammation. The possibility that lactoferrin limits the autodestructive inflammatory responses presents a new alternative for the future management of systemic inflammation.

Animals↗
PubMed1993

Downregulation of neutral endopeptidase (EC 3.4.24.11) in the inflamed rat intestine.

Intestinal inflammation induced by the nematode Trichinella spiralis is accompanied by increased intestinal concentrations of substance P, a mediator of inflammation and a stimulant of smooth muscle contraction, and by intestinal hypermotility. The expression of neutral endopeptidase (NEP), a cell surface enzyme that degrades substance P in the extracellular fluid, was examined in the inflamed intestine. NEP enzymatic activity, measured by a fluorometric assay, was reduced by 84-fold in jejunal mucosa-circular muscle and by 12-fold in jejunal longitudinal muscle-myenteric plexus within 6 days after infection with T. spiralis. The downregulation was unaffected by treatment with betamethasone and was still observed in athymic animals. NEP protein levels, examined by Western blotting, confirmed the loss of NEP from inflamed tissue. The specific activity for degradation of substance P was reduced by sixfold in jejunal mucosa-circular muscle and by twofold in jejunal longitudinal muscle-myenteric plexus of rats infected with T. spiralis compared with uninfected controls. Thus the downregulation of NEP resulted in reduced substance P degradation, which may contribute to functional abnormalities of the inflamed intestine.

Analysis of Variance↗
PubMed2000

Enhanced expression of iNOS in inflamed colons of IL-2-deficient mice does not impair colonic epithelial barrier function.

On the basis of recently observed high levels of iNOS expression that correlated with intestinal inflammation in interleukin-2-deficient [IL-2(-/-)] mice, it was postulated that nitric oxide may damage colonic epithelial cells or impair intestinal epithelial barrier function. This damage may result in an increased permeability of the colonic epithelium leading to high antigenic exposure of the intestinal immune system, which may perpetuate chronic inflammation. Our data demonstrate that high expression of iNOS in IL-2(-/-) mice is correlated with the length/weight ratio (L/W ratio), a widely accepted marker for intestinal inflammation. However, no reduction of epithelial resistance was observed, as would be expected in case of a damaged, leaky epithelium. Our results suggest that enhanced formation of NO in IL-2(-/-) mice does not cause impairment of epithelial barrier function.

Animals↗
PubMed2005

Role of vasoactive intestinal peptide in inflammation and autoimmunity.

Vasoactive intestinal peptide (VIP), a peptide produced by immune cells, exerts a wide spectrum of immunological functions that control the homeostasis of the immune system. In the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, both in innate and adaptive immunity. In innate immunity, this peptide inhibits the production of inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP reduces the expression of co-stimulatory molecules on antigen-presenting cells, and therefore reduces stimulation of antigen-specific CD4 T-cells. In terms of adaptive immunity, VIP promotes T-helper (Th)2-type responses, and reduces inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors are known. Therefore, VIP and its analogs have been proposed as promising alternative candidates to existing therapies for the treatment of acute and chronic inflammatory and autoimmune diseases. The aim of this review is to update knowledge of the cellular and molecular events that are relevant to VIP function in the immune system. The central functions that VIP plays in cellular processes is being recognized and attention is being focused on this important peptide with regard to exciting new candidates for therapeutic intervention and drug development.

Animals↗
PubMed1999

Medium-chain triglycerides modulate ileitis induced by trinitrobenzene sulfonic acid.

BACKGROUND: It is important to develop an appropriate animal model for further investigation into inflammatory bowel disease (IBD). We therefore investigated a trinitrobenzene sulfonic acid (TNBS) ileitis model. Dietary fat in Crohn's disease is still a controversial risk factor for IBD. We therefore also studied the effects of medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) on TNBS ileitis. METHODS AND RESULTS: An intraileal injection of TNBS induced ulceration and inflammation with thickening of the intestinal wall, which were characterized histologically by infiltration of polymorphic nuclear leucocytes and by granuloma formation. The mucosal damage score and serum sialic acid levels reached their highest 7 days after the TNBS injection and then gradually decreased. The mucosal damage series in the MCT group was significantly lower than in the LCT group, and levels of tumour necrosis factor-alpha (TNF-alpha) and leukotriene B4 (LTB4) tended to be lower in the MCT group. CONCLUSIONS: These results suggested that TNBS enteritis might be useful as an IBD animal model and that MCT modulates intestinal inflammation and is less damaging than LCT.

Analysis of Variance↗
PubMed2005

Down-regulation of the anti-inflammatory protein annexin A1 in cystic fibrosis knock-out mice and patients.

Cystic fibrosis is a fatal human genetic disease caused by mutations in the CFTR gene encoding a cAMP-activated chloride channel. It is characterized by abnormal fluid transport across secretory epithelia and chronic inflammation in lung, pancreas, and intestine. Because cystic fibrosis (CF) pathophysiology cannot be explained solely by dysfunction of cystic fibrosis transmembrane conductance regulator (CFTR), we applied a proteomic approach (bidimensional electrophoresis and mass spectrometry) to search for differentially expressed proteins between mice lacking cftr (cftr(tm1Unc), cftr-/-) and controls using colonic crypts from young animals, i.e. prior to the development of intestinal inflammation. By analyzing total proteins separated in the range of pH 6-11, we detected 24 differentially expressed proteins (>2-fold). In this work, we focused on one of these proteins that was absent in two-dimensional gels from cftr-/- mice. This protein spot (molecular mass, 37 kDa; pI 7) was identified by mass spectrometry as annexin A1, an anti-inflammatory protein. Interestingly, annexin A1 was also undetectable in lungs and pancreas of cftr-/- mice, tissues known to express CFTR. Absence of this inhibitory mediator of the host inflammatory response was associated with colonic up-regulation of the proinflammatory cytosolic phospholipase A2. More importantly, annexin A1 was down-regulated in nasal epithelial cells from CF patients bearing homozygous nonsense mutations in the CFTR gene (Y122X, 489delC) and differentially expressed in F508del patients. These results suggest that annexin A1 may be a key protein involved in CF pathogenesis especially in relation to the not well defined field of inflammation in CF. We suggest that decreased expression of annexin A1 contributes to the worsening of the CF phenotype.

Adolescent↗
PubMed2001

Impact of LKM512 yogurt on improvement of intestinal environment of the elderly.

Improvement of the intestinal environment by administration of LKM512 yogurt was examined using polyamine, haptoglobin and mutagenicity as indexes which directly reflect the health condition of the host. The concentration of spermine in feces increased significantly by 3-fold (P<0.05) at week 2 of administration of LKM512 yogurt compared with before administration, and that of putrescine, spermidine, and cadaverine also tended to increase with administration of LKM512 yogurt. The haptoglobin content in feces decreased significantly (P<0.05) at week 2 of administration of LKM512 yogurt, and it showed a negative correlation with the polyamine content, indicating that acute intestinal inflammation was suppressed. Fecal mutagenicity was measured using fecal extract and fecal precipitate. Both preparations showed similar significant decreases (P<0.05) by the administration of LKM512 yogurt, as well as a negative correlation with polyamine content. This result indicated that antimutagenicity due to administration of LKM512 yogurt was not based on binding of the mutagen to the bacterial cell wall. Many reports have suggested that polyamines increased by the administration of LKM512 yogurt led to inhibition of inflammation and antimutagenicity in the intestinal tract.

Aged↗
PubMed2005

Propionibacterium freudenreichii component 1.4-dihydroxy-2-naphthoic acid (DHNA) attenuates dextran sodium sulphate induced colitis by modulation of bacterial flora and lymphocyte homing.

BACKGROUND AND AIMS: 1.4-Dihydroxy-2-naphthoic acid (DHNA), a bifidogenic growth stimulator from Propionibacterium freudenreichii, is thought to have a beneficial effect as a prebiotic; however, its in vivo effect on intestinal inflammation remains unknown. The aim of this study was to determine whether oral administration of DHNA can ameliorate dextran sodium sulphate (DSS) induced colitis and to determine the possible underlying mechanisms. METHOD: Colitis was induced in mice by treatment with 2.0% DSS for seven days. DHNA (0.6 or 2.0 mg/kg) was given in drinking water prior to (preventive study) or after (therapeutic study) DSS administration. Colonic damage was histologically scored, and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) expression and beta7 positive cell infiltration were determined by immunohistochemistry. mRNA levels of proinflammatory cytokines (interleukin (IL)-1beta, IL-6 and tumour necrosis factor alpha (TNF-alpha)) were determined by quantitative real time polymerase chain reaction. In addition, bacterial flora in the caecum, concentrations of short chain acids, and luminal pH were examined. RESULTS: DHNA improved survival rate and histological damage score in mice administered DSS in both the preventive and therapeutic studies. DHNA significantly attenuated the enhanced expression of MAdCAM-1, the increased beta7 positive cell number, and the increased mRNA levels of IL-1beta, IL-6, and TNF-alpha in DSS treated colon. In addition, the decreased number of Lactobacillus and Enterobacteriaceae induced by DSS was recovered by DHNA. Preventive effects on decrease in butyrate concentration and decrease in pH level in mice administered DSS were also observed in the DHNA preventive study. CONCLUSION: DHNA, a novel type of prebiotic, attenuates colonic inflammation not only by balancing intestinal bacterial flora but also by suppressing lymphocyte infiltration through reduction of MAdCAM-1.

Animals↗