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At least 199 records · Page 11Linked to original sources
PubMed2000

Nuclear factor-kappa B activity and intestinal inflammation in dextran sulphate sodium (DSS)-induced colitis in mice is suppressed by gliotoxin.

In acute DSS-induced colitis nuclear factor (NF)-kappaB-dependent inflammatory cytokines including IL-1 and tumour necrosis factor-alpha (TNF-alpha) are up-regulated. Here we examined the effects of gliotoxin, a fungal metabolite known to inhibit NF-kappaB activity, on cytokine production by a mouse cell system in vitro and on intestinal inflammation and NF-kappaB activation in vivo. In vitro gliotoxin decreased TNF-alpha gene expression and protein production by RAW-264.7 mouse macrophage-like cells stimulated with lipopolysaccharide. In vivo, gliotoxin treatment of mice was begun on day 3 of 5% DSS application dissolved in the drinking water and continued until day 8. Gliotoxin treatment dose-dependently down-regulated colonic inflammation as assessed histologically and in parallel there was a suppression of colonic TNF-alpha and IL-1alpha mRNA expression on day 8 as analysed by semiquantitative reverse transcriptase-polymerase chain reaction (P < 0.01). Furthermore, colonic NF-kappaB DNA-binding activity was increased in DSS-induced colitis and was suppressed by gliotoxin. These results demonstrate the essential role of NF-kappaB in DSS-induced colitis and indicate a molecular approach to the treatment of intestinal inflammatory disorders.

Animals↗
PubMed2005

Role of peripheral corticotropin-releasing factor and urocortin II in intestinal inflammation and motility in terminal ileum.

Corticotropin-releasing factor (CRF) and the closely related family of neuropeptides urocortins (Ucns) are ancient paracrine-signaling peptides secreted in both the central and peripheral neural circuits. CRF and Ucns released from the CNS (central) regulate a plethora of physiological processes that include food intake, inflammation, and bowel motility and permeability. In the gastrointestinal tract, CRF actions are largely proinflammatory, whereas the effects of the Ucn subtypes can be either pro- or antiinflammatory. Central (intracerebroventricular) or peripheral (i.p.) administration of CRF or Ucns inhibits gastric emptying and promotes colonic motility. To ascertain the role of peripherally expressed CRF and UcnII in gastrointestinal inflammation and motility, we generated ileum-specific phenotypic knockouts of these peptides by using RNA interference. Long dsRNA effectively silenced basal expression of CRF and UcnII in ileum. Control dsRNA or saline treatment did not affect CRF or UcnII expression. In an experimental model of toxin-induced intestinal inflammation, inhibition of CRF ablated the inflammatory response (measured by epithelial damage, mucosal edema, and neutrophil infiltration). UcnII dsRNA treatment did not alter the inflammatory response to toxin. Furthermore, ileal motility was increased after site-specific inhibition of both CRF and UcnII. Thus, we demonstrate that ileal-specific CRF promotes inflammation and both CRF and UcnII modulate bowel motility.

Analysis of Variance↗
PubMed1999

In vitro activated CD4+ T cells from interferon-gamma (IFN-gamma)-deficient mice induce intestinal inflammation in immunodeficient hosts.

To investigate the role of IFN-gamma in the immunopathogenesis of inflammatory bowel disease (IBD), severe combined immunodeficient (SCID) mice were transplanted with in vitro activated CD4+ T cells from either wild-type (WT) or IFN-gamma-deficient (IFN-gammaKO) BALB/c mice. In vitro, the two types of T cells displayed comparable proliferation rates and production of tumour necrosis factor-alpha (TNF-alpha), IL-2, IL-4 and IL-10 after concanavalin A (Con A) stimulation. When transplanted into SCID mice, WT CD4+ blasts induced a lethal IBD, whereas IFN-gammaKO blasts induced a less severe intestinal inflammation with moderate weight loss. Intracellular cytokine staining of lamina propria lymphocytes (LPL) revealed comparable fractions of CD4+ T cells positive for TNF-alpha, IL-2 and IL-10 in the two groups of transplanted SCID mice, whereas a two-to-three-fold increase in the fraction of IL-4-positive cells was found in IFN-gammaKO-transplanted SCID mice. Flow cytometric analyses showed strong up-regulation of MHC class II expression of colonic epithelial cells of WT-CD4+ T cell-transplanted compared with IFN-gammaKO-transplanted SCID mice. A significantly higher fraction of CD4+ LPL were found to enter the cell cycle, i.e. to incorporate bromo-deoxy-uridine, and to undergo apoptosis in vivo in WT-transplanted compared with IFN-gammaKO-transplanted SCID mice. These data point towards an important role for IFN-gamma in the development of IBD in SCID mice. The inflammation might be initiated and subsequently enhanced by the ability of IFN-gamma to induce de novo MHC class II expression in the colonic epithelium, a change which could lead to increased antigen processing and production of local proinflammatory cytokines, CD4+ T cell turnover and thereby to exaggeration of disease.

Animals↗
PubMed2026

An inflammatory bowel disease-linked lncRNA suppresses transcription factor T-BET expression in T cells to limit intestinal inflammation.

Among the tens of thousands of annotated long noncoding RNAs (lncRNAs) in the human genome, only a small fraction have been functionally characterized. Here, we show that a well-established inflammatory bowel disease (IBD) risk locus encoded a conserved lncRNA, lnc15 (2310015A10Rik/ENSMUSG00000097729), whose structure was destabilized by risk-associated variants, leading to its degradation. Deletion of lnc15 in mice resulted in molecular features of inflammation under steady-state conditions and conferred heightened susceptibility to experimental colitis. Lnc15 was abundantly expressed in T cells, with highest expression in regulatory T (Treg) cells. Mechanistically, lnc15 suppressed the transcription factor T-BET by recruiting the CCR4-NOT RNA degradation complex to Tbx21 mRNA. Our study identifies that lnc15 simultaneously enhances Treg cell suppressive function and impairs conventional T cell pathogenicity in the context of intestinal inflammation. Collectively, these findings identify lnc15 as a functional lncRNA that links noncoding genetic variation to immune regulation and prevention of mucosal inflammation. VIDEO ABSTRACT.

RNA, Long Noncoding↗
PubMed2002

PepT1-mediated fMLP transport induces intestinal inflammation in vivo.

In the present study, the effect of H(+)/peptide transporter (PepT1)-mediated N-formylmethionyl-leucyl-phenylalanine (fMLP) transport on inflammation in vivo in the rat small intestine, which expresses high PepT1 levels, and in the rat colon, which does not express PepT1, were investigated using myeloperoxidase (MPO) activity and histological analysis. We found that 10 microM fMLP perfusion in the jejunum for 4 h significantly increased MPO activity and altered the architecture of jejunal villi. In contrast, 10 microM fMLP perfusion in the colon for 4 h did not induce any inflammation. In addition, we have shown that 50 mM Gly-Gly alone did not affect basal MPO activity but completely inhibited the MPO activity induced by 10 microM fMLP in the jejunum. Together, these experiments demonstrate that 1) the differential expression of PepT1 between the small intestine and the colon plays an important role in epithelial-neutrophil interactions and 2) the inhibition of fMLP uptake by jejunal epithelial cells (expressing PepT1) reduces the neutrophil ability to move across the epithelium, in agreement with our previously published in vitro study. This report constitutes the first in vivo study showing the implication of a membrane transporter (PepT1) in intestinal inflammation.

Animals↗
PubMed2002

Amelioration of chronic and spontaneous intestinal inflammation with an antisense oligonucleotide (ISIS 9125) to intracellular adhesion molecule-1 in the HLA-B27/beta2 microglobulin transgenic rat model.

Adhesion molecules are known to be an important part of leukocyte migration and extravasation in both homeostatic and inflammatory conditions. Intracellular adhesion molecule-1 (ICAM-1 or CD54) is constitutively expressed on endothelial cells and is up-regulated during acute and chronic inflammation. We investigated the efficacy and consequences of interfering with CD54 after administration of an antisense oligonucleotide to ICAM-1 (CD54) in the transgenic HLA-B27/beta2 microglobulin rat model. One hundred percent of the HLA-B27 transgene + animals will spontaneously develop chronic inflammation (some more severely than others) in the gastric mucosa, cecum, and colon. We carried out two studies, i.p. injection and rectal administration of antisense. Following i.p. and rectal treatment, there were significant decreases in colonic mucosal wall thickness, histologic inflammation, CD54 expression in the colon and peripheral blood, and the percentage of colon weight per end body weight. Furthermore, decreased expression of CD49d, CD18, and tumor necrosis factor-alpha was observed in antisense treated rats. Therefore, the HLA-B27 transgenic model of spontaneous and chronic inflammatory bowel disease, which has increased expression of adhesion molecules, responds to both routes of administration of ICAM-1 antisense oligonucleotides. These studies support the regulatory role of adhesion molecules in chronic intestinal inflammation, the need for an understanding of how the route of drug delivery can alter the dose and area affected, and finally the role of antisense oligonucleotides as a therapeutic modality in chronic spontaneous inflammatory bowel diseases.

Administration, Rectal↗
PubMed1999

Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens.

We generated transgenic mice for STAT-4, a regulatory protein specifically associated with IL-12 signaling, under the control of a CMV promoter. These mice expressed strikingly increased nuclear STAT-4 levels in lamina propria CD4+ T lymphocytes upon systemic administration of dinitrophenyl-keyhole limpet hemocyanin and developed chronic transmural colitis characterized by infiltrates of mainly CD4+ T lymphocytes. The latter cells produced predominantly TNF and IFN-gamma but not IL-4 upon activation with alphaCD3/CD28 or autologous bacterial Ags, consistent with a Th1-type cell response. Furthermore, chronic colitis in STAT-4 transgenic mice could be adoptively transferred to SCID mice by colonic and splenic CD4+ T cells that were activated with Ags from autologous bacterial flora. These data establish a critical molecular signaling pathway involving STAT-4 for the pathogenesis of chronic intestinal inflammation, and targeting of this pathway may be relevant for the treatment of colitis in humans.

Adoptive Transfer↗
PubMed2002

Interleukin-1beta converting enzyme (caspase-1) in intestinal inflammation.

An imbalance of T helper cell type 1 (Th1) versus type 2 (Th2) polarization in favor of Th1 cell subsets appears to be a key pathogenic mechanism in chronic inflammatory bowel disease (IBD), in particular in Crohn's disease. The interferon gamma-inducing factor interleukin (IL)-18 acts in strong synergism with the Th1 polarizing cytokine IL-12. Recent studies provide evidence for the participation of IL-18 in the pathogenesis of IBD: IL-18 expression is increased in inflamed lesions of Crohn's disease patients and neutralization of IL-18 in different models of experimental colitis resulted in a dramatic amelioration of disease severity. IL-18 and IL-1beta are cleaved and thereby activated by the interleukin-1beta converting enzyme (ICE). Activation of ICE also occurs during different types of infectious colitis, and ICE expression and subsequent release of IL-1beta and IL-18 significantly contribute to intestinal inflammation. ICE knockout mice as well as mice treated with the ICE inhibitor pralnacasan are protected against experimental mucosal inflammation. Thus, inhibition of ICE represents an intriguing new target that requires further investigation in animal models.

Animals↗
PubMed2005

Mu opioid receptor expression is increased in inflammatory bowel diseases: implications for homeostatic intestinal inflammation.

BACKGROUND AND AIMS: Recent studies with mu opioid receptor (MOR) deficient mice support a physiological anti-inflammatory effect of MOR at the colon interface. To better understand the potential pharmacological effect of certain opiates in inflammatory bowel diseases (IBD), we (1) evaluated the regulation in vivo and in vitro of human MOR expression by inflammation; and (2) tested the potential anti-inflammatory function of a specific opiate (DALDA) in inflamed and resting human mucosa. PATIENTS AND METHODS: Expression of MOR mRNA and protein was evaluated in healthy and inflamed small bowel and colonic tissues, isolated peripheral blood mononuclear cells and purified monocytes, and CD4+ and CD8+ T cells from healthy donors and IBD patients. The effect of cytokines and nuclear factor kappaB (NFkappaB) activation on MOR expression in lymphocyte T and monocytic human cell lines was assessed. Finally, DALDA induced anti-inflammatory effect was investigated in mucosal explants from controls and IBD patients. RESULTS: MOR was expressed in ileal and colonic enteric neurones as well as in immunocytes such as myeloid cells and CD4+ and CD8+ T cells. Overexpressed in active IBD mucosa, MOR was significantly enhanced by cytokines and repressed by NFkappaB inhibitor in myeloid and lymphocytic cell lines. Furthermore, ex vivo DALDA treatment dampened tumour necrosis factor alpha mRNA expression in the colon of active IBD patients. CONCLUSIONS: Given the increased expression of MOR and the ex vivo beneficial effect of DALDA in active IBD, natural and/or synthetic opioid agonists could help to prevent overt pathological intestinal inflammation.

Adult↗
PubMed2001

Regulation of murine intestinal inflammation by reactive metabolites of oxygen and nitrogen: divergent roles of superoxide and nitric oxide.

Several reports have implicated reactive oxygen and nitrogen metabolites (RONS) in the initiation and/or progression of inflammatory bowel diseases (IBDs). We have investigated the role of three key RONS-metabolizing enzymes (inducible nitric oxide synthase [iNOS], superoxide dismutase [SOD], nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) in a murine model of IBD. Mice genetically deficient ((-/-)) in either iNOS or the p47phox subunit of NADPH oxidase, transgenic (Tg) mice that overexpress SOD, and their respective wild-type (WT) littermates were fed dextran sulfate sodium (DSS) in drinking water for 7 days to induce colitis. In addition, the specific iNOS inhibitor 1400W was used in DSS-treated WT and p47phox(-/-) mice. WT mice responded to DSS feeding with progressive weight loss, bloody stools, elevated serum NO(X) and colonic mucosal injury with neutrophil infiltration. Both the onset and severity of colitis were significantly attenuated in iNOS(-/-) and 1400W-treated WT mice. While the responses to DSS did not differ between WT and p47phox(-/-) mice, enhanced protection was noted in 1400W-treated p47phox(-/-) mice. Interestingly, SOD(Tg) mice exhibited more severe colitis than their WT littermates. These findings reveal divergent roles for superoxide and iNOS-derived NO in intestinal inflammation.

Amidines↗
PubMed2005

TGF-beta1 production by CD4+ CD25+ regulatory T cells is not essential for suppression of intestinal inflammation.

Naturally occurring CD4+ CD25+ regulatory T cells (Treg) are potent suppressors of CD4+ and CD8+ T cell responses in vitro and inhibit several organ-specific autoimmune diseases. While most in vitro studies suggest that CD4+ CD25+ Treg cells adopt a cytokine-independent but cell contact-dependent mode of T cell regulation, their precise mechanism of suppression in vivo remains largely unknown. Here we examine the functional contribution of Treg cell-derived TGF-beta1 and effector T cell responsiveness to TGF-beta in CD4+ CD25+ T cell-mediated suppression of inflammatory bowel disease (IBD). We show that CD4+ CD25+ Treg cells from either TGF-beta1+/+ or neonatal TGF-beta1-/- mice can suppress the incidence and severity of IBD as well as colonic IFN-gamma mRNA expression induced by WT CD4+ CD25- effector T cells. Furthermore, TGF-beta-resistant Smad3-/- CD4+ CD25+ Treg cells are equivalent to WT Treg cells in their capacity to suppress disease induced by either WT or Smad3-/- CD4+ CD25- effector T cells. Finally, anti-TGF-beta treatment exacerbates the colitogenic potential of CD4+ CD25- effector T cells in the absence of CD4+ CD25+ Treg cells. Together, these data demonstrate that in certain situations CD4+ CD25+ T cells are able to suppress intestinal inflammation by a mechanism not requiring Treg cell-derived TGF-beta1 or effector T cell/Treg cell responsiveness to TGF-beta via Smad3.

Adoptive Transfer↗
PubMed2000

Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.

The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.

Adult↗
PubMed2004

Interleukin-10 knockout mouse: a model for studying bone metabolism during intestinal inflammation.

The objective was to compare bone mass (bone mineral content [BMC], bone mineral density [BMD]) and biomechanical strength of femurs and lumbar vertebrae from male and female wild-type (WT) and IL-10 knockout (KO) mice to determine if the IL-10 KO mouse model is appropriate for studying inflammation-associated bone abnormalities and potential interventions. Offspring from IL-10 KO and WT mice (n = 15 to 19 mice/gender per group) were studied until 13 weeks of age. IL-10 KO mice had a higher (P < 0.05) colonic histologic injury score and serum proinflammatory cytokines (IL-6, IL-1beta, TNF-alpha) than WT mice. IL-10 KO mice also experienced bone abnormalities as femur and verterbral BMC and BMD were lower (P < 0.05) compared with WT mice. Moreover, some biomechanical strength parameters such as femur yield load (P = 0.057) and resilience (P < 0.05) and peak load of lumbar vertebra 3 (P < 0.05) were lower than WT mice. Due to differences in body size, males had greater (P < 0.05) femur and vertebral bone mass as well as femur weight, length, yield load, resilience, and peak load than females. A significant interaction (genotype x gender) was only observed for femur resilience in which male WT mice had a greater (P = 0.009) resilience than all other groups. These results demonstrate that IL-10 KO mice develop bone abnormalities that accompany intestinal inflammation and elevated serum proinflammatory cytokines. Thus, the IL-10 KO mouse model may be useful for studying inflammation-associated bone abnormalities and potential therapeutic interventions.

Animals↗
PubMed2006

Aggravation of intestinal inflammation by depletion/deficiency of gammadelta T cells in different types of IBD animal models.

The role of gammadelta T cells in inflammatory bowel disease (IBD) is still controversial. Although gammadelta T cells induce IBD in immunodeficient animals, others suggest a protective role of gammadelta T cells. Therefore, this study was conducted in order to elucidate the effect of gammadelta T cell depletion/deficiency on different IBD animal models. Mice depleted of or deficient in gammadelta T cells were exposed to dextran sodium sulfate (DSS) in order to induce colitis. In addition, gammadelta T cells were depleted in mice with terminal ileitis (TNFDeltaARE) or colitis due to interleukin 2 deficiency (IL-2 ko). Finally, DSS-induced colitis was studied in mice deficient in interferon gamma (IFN-gamma ko) upon gammadelta T cell depletion. Depletion of gammadelta T cells aggravated DSS-induced colitis and terminal ileitis of TNFDeltaARE mice. Exacerbated DSS-induced colitis was also found in gammadelta T cell-deficient mice. IL-2 ko mice showed increased mortality upon early (starting at 4 wk of age) but not late depletion (starting at 8 wk of age). Early gammadelta T cell depletion or deficiency resulted in increased IFN-gamma production by both lamina propria lymphocytes and splenocytes in every model investigated herein. In IFN-gamma ko mice, gammadelta T cell depletion did not affect the development and course of DSS-induced colitis. The protective effect of gammadelta T cells in IBD was confirmed in various IBD animal models. Particularly, during the early phase of intestinal inflammation, gammadelta T cells appear to be important. The mechanism seems to involve the control of IFN-gamma production and epithelial regeneration.

Animals↗
PubMed2001

Persistent epithelial dysfunction and bacterial translocation after resolution of intestinal inflammation.

Epithelial secretion may play an important role in reducing bacterial colonization and translocation in intestine. If so, secretory dysfunction could result in increased susceptibility to infection and inflammation. We investigated whether long-term colonic secretory dysfunction occurs after a bout of colitis and if this is accompanied by an increase in bacterial colonization and translocation. Rats were studied 6 wk after induction of colitis with trinitrobenzene sulfonic acid when inflammation had completely resolved, and epithelial permeability was normal. Intestinal loops were stimulated with either Clostridium difficile toxin A or a phosphodiesterase inhibitor. In vitro, colonic tissue from previously sensitized rats was exposed to antigen (ovalbumin). Secretory responses to all three stimuli were suppressed in rats that had previously had colitis. These rats exhibited increased (16-fold) numbers of colonic aerobic bacteria and increased (>3-fold) bacterial translocation, similar to results in rats studied after resolution of enteritis. Postcolitis bacterial translocation was prevented by daily treatment with an inhibitor of inducible nitric oxide synthase. This study demonstrates that intestinal inflammation results in prolonged impairment of colonic epithelial secretion, which may contribute to increases in bacterial load and bacterial translocation. Epithelial dysfunction of this type could underlie an increased propensity for further bouts of inflammation, a hallmark of diseases such as inflammatory bowel disease.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Helicobacter hepaticus-induced colitis in interleukin-10-deficient mice: cytokine requirements for the induction and maintenance of intestinal inflammation.

We have previously shown that specific-pathogen-free interleukin-10 (IL-10)-deficient (IL-10 KO) mice reconstituted with Helicobacter hepaticus develop severe colitis associated with a Th1-type cytokine response. In the present study, we formally demonstrate that IL-12 is crucial for disease induction, because mice deficient for both IL-10 and IL-12 p40 show no intestinal pathology following H. hepaticus infection. By using monoclonal antibodies (MAbs) to IL-12, gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha), we have further analyzed the role of these cytokines in the maintenance of the Th1 response and inflammation in IL-10 KO mice with established H. hepaticus-induced colitis. Treatment of infected colitic IL-10 KO mice with anti-IL-12 p40 resulted in markedly reduced intestinal inflammation, colonic IFN-gamma, TNF-alpha, and inducible nitric oxide synthase (iNOS) mRNA levels, and H. hepaticus-specific IFN-gamma secretion by mesenteric lymph node (MLN) cells compared to the findings in control MAb-treated mice. Moreover, the diminished pathology was associated with decreased numbers of colonic CD3(+) T cells and significantly reduced frequencies of Helicobacter-reactive CD4(+) Th1 cells in MLN. In contrast, anti-IFN-gamma and/or anti-TNF-alpha had no effect on intestinal inflammation in IL-10 KO mice with established colitis. Using IL-10/IFN-gamma double-deficient mice, we further show that IFN-gamma is not required for the development of colitis following H. hepaticus infection. MLN cells from infected IL-10/IFN-gamma KO animals secreted elevated amounts of IL-12 and TNF-alpha following bacterial antigen stimulation, indicating alternative pathways of disease induction. Taken together, our results demonstrate a crucial role for IL-12 in both inducing and sustaining intestinal inflammation through recruitment and maintenance of a pool of pathogenic Th1 cells.

Animals↗
PubMed2001

Recombinant human interleukin-11 restores smooth muscle function in the jejunum and colon of human leukocyte antigen-B27 rats with intestinal inflammation.

Recombinant human interleukin (rhIL)-11 has anti-inflammatory and protective effects in models of intestinal mucosal injury. Our aim was to investigate whether oral treatment with rhIL-11 reverses functional abnormalities in intestinal muscle contractility resulting from human leukocyte antigen (HLA)-B27-dependent gut inflammation. Isometric contractions were studied in jejunal and colonic longitudinal muscles. Muscle strips were isolated from HLA-B27 transgenic rats with spontaneous inflammation following treatment with enteric-coated rhIL-11 multiparticulates (500 microg/kg) or placebo multiparticulates given orally every 48 h for 2 weeks. Myeloperoxidase (MPO) activity was measured in intestinal tissue samples and served as an index of inflammation. Colonic damage was also assessed histologically. The HLA-B27 rats receiving placebo had chronic diarrhea, and MPO activity was increased in the jejunum and colon. Intestinal inflammation was associated with a decreased ability of the muscles to generate active tension in response to electrical field stimulation, carbachol, or high KCl. In the jejunum of placebo-treated HLA-B27 rats, concentration-effect curves for carbachol were shifted to lower concentrations yielding a higher EC50. Oral treatment of HLA-B27 rats with rhIL-11 suppressed the symptoms of diarrhea, normalized MPO activity, and improved the colonic damage score. Simultaneously, neurally mediated responses were improved and the maximal tension generated by carbachol or KCl was normalized in the jejunum and colon. The EC50 for carbachol in the jejunum of HLA-B27 rats was also normalized by rhIL-11 treatment. Our data demonstrate that oral administration of enteric-coated rhIL-11 suppresses intestinal inflammation and reverses intestinal smooth muscle dysfunction in HLA-B27 transgenic rats.

Animals↗
PubMed2002

Mechanisms of active intestinal inflammation and potential down-regulation via lipoxins.

Chronic inflammatory diseases of the intestine (i.e. Crohn's and chronic ulcerative colitis- collectively known as inflammatory bowel disease [IBD]) are a very significant public health problem in the United States and other industrialized nations. Thus, effort has been made toward understanding the biological mechanisms that regulate such inflammation. Largely, these efforts have focused on identifying the mechanisms that mediate activation of inflammation and have succeeded in identifying a variety of signaling pathways by which a wide range of agonists can activate a mucosal immune inflammatory response. Playing a central role in many of these pathways is the intestinal epithelium, which serves as a barrier to, and interfaces with the outside world. However, recent studies have shown that not only can some agonists activate pro-inflammatory signals in intestinal epithelial cells, but other agonists can activate "anti-inflammatory" signals in these cells that dampen the responses to pro-inflammatory agonists. One such anti-inflammatory agonist is the eicosanoid lipoxin A4 (LXA4). Specifically, LXA4, its epimer 15-LXA4, and their analogs potently down-regulate defining and causative events of intestinal inflammation in an in vitro model. These compounds are now being tested for their ability to down-regulate inflammation in mouse models of colitis and may ultimately prove to be of significant benefit to individuals suffering from debilitating chronic inflammatory intestinal disorders.

Fatty Acids, Unsaturated↗