Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Toll-like receptor (TLR) and nucleotide-binding oligomerization domain (Nod) families of proteins are critical for bacterial recognition, and, acutely, this frequently leads to proinflammatory responses. Polymorphisms in Nod2 (CARD 15) are associated with an increased likelihood of developing Crohn's disease. However, it is not yet clear how Nod2 dysfunctions lead to defects in human intestinal immune homeostasis. Studies to date have focused on functions after acute, rather than chronic, Nod2 stimulation. However, the intestine is an environment of chronic bacterial product exposure with tolerance to luminal flora. We therefore hypothesized that long-term Nod2 stimulation contributes to down-regulation of inflammatory responses from innate immune receptors. We found that pretreatment with muramyl dipeptide (MDP), a ligand for Nod2, significantly decreased production of the proinflammatory cytokines TNF-alpha, IL-8, and IL-1beta upon Nod2, TLR4, and TLR2 restimulation in primary human monocyte-derived macrophages from a large cohort of individuals. Importantly, TNF-alpha-induced production of proinflammatory cytokines remained intact in these same cells. MDP-stimulated macrophages from Crohn's disease-relevant Leu1007insC Nod2 homozygote individuals were deficient in their ability to cross-tolerize to subsequent treatment with TLR2 and TLR4 ligands. We show that acute Nod2 stimulation induced IRAK-1 activation, and that chronic MDP treatment down-regulated IRAK-1 activation upon Nod2 or TLR4 restimulation. In a subset of individuals, chronic Nod2 stimulation induced expression of the IRAK-1 inhibitory protein IRAK-M. Significantly, intestinal macrophages exhibit tolerance to MDP per production of inflammatory cytokines. These results illustrate a role for chronic stimulation of Nod2 in mediating tolerance to bacterial products.
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PMID:Chronic stimulation of Nod2 mediates tolerance to bacterial products. 1803 8

To determine the genetic program mediating and maintaining the change from susceptibility to Crohn's disease (CD) to ongoing tissue destruction and loss of function, we utilized Affymetrix HG U95 AV2 Gene Chips and analyzed unpooled surgical CD colon specimens from adult patients. Using the patient as his own genetic filter we examined involved versus uninvolved adjacent areas, comparing results within one individual and then performing analysis comparing results between four individuals. Our results interrogated twice as many genes than the previous studies that used pooled unmatched specimens. We identified a limited set of nine genes upregulated in all four patients, and one gene (PTN) as downregulated. Several of the genes, including DEFA6, PAP, REG1A, REG1B, and phospholipase A2 had been implicated in previous studies, supporting their key role in CD. In 3 of 4 patients, 24 genes were upregulated in diseased areas, including DEFA5, IL-8, MMP-1, S100 calcium binding protein, and MGSA. Additional new candidate genes were identified, including DMT1, SERPINA1, GW112, and iNOS. The use of the unpooled samples allowed the detection of significant interindividual differences in expression of many other genes, supporting disease heterogeneity in CD. Results with select genes were confirmed with RT-PCR studies, as well as on biopsy samples from pediatric patients. We have determined a common profile of "late" CD, and also demonstrated the potential variability, suggesting possible differences in etiology, triggers, and the need for more individualized management. Additional studies to investigate protein expression of these candidate genes should be undertaken.
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PMID:Gene expression profiles of late colonic Crohn's disease. 1808 81

Gout is caused by monosodium urate (MSU) crystal-induced inflammation of the joints and periarticular tissues. MSU crystals activate the NOD-like receptor (NLR) NALP3, which functions as a pattern recognition receptor (PRR). Activated NALP3 mediates interleukin-1b (IL-1b) generation from its inactive pro-form, resulting in the activation of further cells and an IL-8-mediated neutrophil influx into the joint. Based on these new findings on the pathophysiology of gout, an open pilot study has recently demonstrated successful treatment of gout with the soluble IL-1R antagonist anakinra in 10 patients. The physiological role of MSU crystals might be that of a danger signal in peripheral tissues, where they stimulate dendritic cell maturation. The role of PRRs such as the NLR is underlined by NALP3 mutations causing hereditary autoinflammatory syndromes and NOD2 polymorphisms as genetic risk factors for Crohn's disease. In addition to the recognition of danger-associated molecular patterns (e.g. MSU), PRRs confer autoantigen recognition and activation of the innate and adaptive immune system in autoimmune diseases. Detection of RNA and DNA-containing immune complexes by toll-like receptors inducing B-cell activation in systemic lupus erythematosus and of proteinase 3 by the protease-activated receptor-2 inducing dendritic cell maturation in Wegener's granulomatosis have recently been reported.
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PMID:[New aspects of the pathogenesis of gout. Danger signals, autoinflammation and beyond]. 1829 53

Angiogenesis is the growth of new blood vessels. In the two major forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, robust angiogenesis exists, and its blockade may have therapeutic potential, as shown in animal models of experimental intestinal inflammation. While abundant literature is available on the positive regulators of intestinal pathological angiogenesis, e.g. VEGF, b-FGF, IL-8, CD40 and CD40L, almost no data exist on negative regulators. Thrombospondin-1 is a negative regulator of angiogenesis, and it plays a new role in IBD-associated angiogenesis. In addition, recombinant thrombospondin-1 may inhibit pathological angiogenesis and may offer a new therapeutic approach to intestinal inflammation.
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PMID:Negative regulators of angiogenesis in inflammatory bowel disease: thrombospondin in the spotlight. 1833 36

Recently we identified galectin-3 (gal-3), which is secreted by colonic epithelial cells (CEC), to be a strong activator of colonic lamina propria fibroblasts (CLPF). Modulation of CLPF function may play a role during stricture and fistula formation in inflammatory bowel disease (IBD). Therefore, we investigated further the expression of gal-3 and effects on CLPF. The aim of this study is to perform a direct comparison of gal-3 between tissue from healthy controls and from patients with either Crohn's disease (CD) or ulcerative colitis (UC). CEC, CLPF and intestinal macrophages (IMAC) were isolated from control and IBD colonic tissue. Interleukin-8 secretion as a readout of CLPF activation was quantified by enzyme-linked immunosorbent assay. Gal-3 in cell cultures and tissue samples was evaluated by Western blot, immunofluorescence and immunohistochemistry. CLPF-migration was assayed in the 48-well modified Boyden chamber. Gal-3 expression was found in all segments of the colon. In the terminal ileum, less gal-3 was found compared with the colon. Immunohistochemistry and immunofluorescence revealed a homogenous distribution of gal-3 in CEC and IMAC of control mucosa and UC. However, significantly less gal-3 was found in IMAC from CD patients. In CD fistulae and stenoses, gal-3 expression was reduced significantly and barely detectable. In co-incubation studies lactose reduced significantly the CLPF-stimulatory potential of gal-3, indicating that the C-terminal domain of gal-3 is responsible for CLPF activation. Gal-3 stimulated CLPF migration in CLPF derived from fistulae. In conclusion, gal-3 expression is down-regulated in CD-fistulae and stenoses as well as in IMAC in CD patients. Gal-3 induces migration of CLPF derived from fistulae. Its role for stricture and fistula formation warrants further investigation.
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PMID:Regulation of galectin-3 function in mucosal fibroblasts: potential role in mucosal inflammation. 1833 93

Populations in high infectious exposure countries are at low risk of some immune-mediated diseases such as Crohn's disease and allergy. This low risk is maintained upon immigration to an industrialized country, but the offspring of such immigrants have a higher immune-mediated disease risk than the indigenous population. We hypothesize that early life exposures in a developing country shape the maternal immune system, which could have implications for the offspring born in a developed country with a low infectious load. The aim of this study was to investigate if exposures in childhood (indicated by country of origin) and subsequent exposures influence immunologic characteristics relevant to stimulation of offspring. Breast milk components among 64 mothers resident in Sweden, 32 of whom immigrated from a developing country, were examined using the ELISA and Cytometric Bead Array methods. Immigrants from a developing country had statistically significantly higher levels of breast milk interleukin-6 (IL-6), IL-8 and transforming growth factor-beta1. A larger number of previous pregnancies were associated with down-regulation of several substances, statistically significant for soluble CD14 and IL-8. The results suggest that maternal country of birth may influence adult immune characteristics, potentially relevant to disease risk in offspring. Such a mechanism may explain the higher immune-mediated disease risk among children of migrants from a developing to developed country. Older siblings may influence disease risk through the action of previous pregnancies on maternal immune characteristics.
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PMID:Maternal country of birth and previous pregnancies are associated with breast milk characteristics. 1848 63

A decrease in the abundance and biodiversity of intestinal bacteria within the dominant phylum Firmicutes has been observed repeatedly in Crohn disease (CD) patients. In this study, we determined the composition of the mucosa-associated microbiota of CD patients at the time of surgical resection and 6 months later using FISH analysis. We found that a reduction of a major member of Firmicutes, Faecalibacterium prausnitzii, is associated with a higher risk of postoperative recurrence of ileal CD. A lower proportion of F. prausnitzii on resected ileal Crohn mucosa also was associated with endoscopic recurrence at 6 months. To evaluate the immunomodulatory properties of F. prausnitzii we analyzed the anti-inflammatory effects of F. prausnitzii in both in vitro (cellular models) and in vivo [2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced] colitis in mice. In Caco-2 cells transfected with a reporter gene for NF-kappaB activity, F. prausnitzii had no effect on IL-1beta-induced NF-kappaB activity, whereas the supernatant abolished it. In vitro peripheral blood mononuclear cell stimulation by F. prausnitzii led to significantly lower IL-12 and IFN-gamma production levels and higher secretion of IL-10. Oral administration of either live F. prausnitzii or its supernatant markedly reduced the severity of TNBS colitis and tended to correct the dysbiosis associated with TNBS colitis, as demonstrated by real-time quantitative PCR (qPCR) analysis. F. prausnitzii exhibits anti-inflammatory effects on cellular and TNBS colitis models, partly due to secreted metabolites able to block NF-kappaB activation and IL-8 production. These results suggest that counterbalancing dysbiosis using F. prausnitzii as a probiotic is a promising strategy in CD treatment.
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PMID:Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. 2355 27

The innate immune response to enteropathogenic bacteria includes chemokine-induced polymorphonuclear neutrophil (PMN) migration across mucosal epithelia leading to bacterial clearance and resolution of infection. Among these bacteria, diffusely adherent Escherichia coli expressing Afa/Dr fimbriae (Afa/Dr DAEC), causing childhood diarrhea, can promote IL-8-dependent PMN transmigration across cultured intestinal epithelial cell monolayers via MAPK pathway activation. However, interactions between PMN and Afa/Dr DAEC are poorly documented and constitute the aim of the present study. Using the human PLB-985 cell line differentiated into fully mature PMN, we described the coordinated response to various E. coli. The rapid and strong release of reactive oxygen species and preformed intragranular mediators (myeloperoxidase and IL-8) is followed by a later TNF-alpha, IL-1beta, and IL-8 synthesis. The use of wild-type (IH11128, C1845, LF82), control (AAEC185), and recombinant (AAEC185 bearing Dr or F1845 fimbriae, AdLF82, or type 1 pili) bacterial strains allowed us to demonstrate that late IL-8 hyperproduction is triggered by type 1 pili but not by Dr or F1845 fimbriae; MAPKs (p38, ERK, Src) and NF-kappaB activations are implicated in this response. Thus, in the course of Afa/Dr DAEC intestinal infection, epithelium- and neutrophil-derived IL-8 could, at least in part, control the flow of neutrophils through the lamina propria. Afa/Dr DAEC-induced IL-8 hyperproduction by PMN might thus be important for inducing and perpetuating local inflammation, and this self-amplifying loop might play a role in the pathogenesis of inflammatory bowel diseases such as Crohn's disease.
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PMID:Escherichia coli type 1 pili trigger late IL-8 production by neutrophil-like differentiated PLB-985 cells through a Src family kinase- and MAPK-dependent mechanism. 1901 76

Mycobacterium avium subspecies paratuberculosis (MAP) is a facultative intracellular organism that resides in host macrophages. MAP causes a fatal wasting syndrome in ruminants, typified by granulomatous enteritis in the small intestine. MAP has also been suspected as a causative or exacerbating factor in some cases of human Crohn's disease. In MAP infections, a cytotoxic and proinflammatory Th1-like response is essential to control disease. While such a response may initially develop, this typically gives way to a Th2-like response later in infection. Interaction between CD40 receptors on macrophages and CD154 (CD40L) on activated T cells is crucial for maintaining a Th1 response and activation of macrophages. In this report, we investigated the hypothesis that CD40 signalling is impaired in MAP-infected macrophages. Uninfected bovine monocyte-derived macrophages (MDM) responded to CD40L by up-regulating expression of genes encoding IL-6, TNFalpha, IL-8, iNOS, IL-10, and IL-12p40. In contrast, MDM cells infected with MAP failed to up-regulate expression of iNOS and IL-12p40 genes in response to CD40L. CD40L stimulation caused a transient activation of the mitogen-activated protein kinase (MAPK) family member extracellular signal-regulated kinases (ERK) 1/2, stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) and p38 in MDM cells. In uninfected cells, inhibition of MAPK revealed that CD40L-mediated increase in IL-6 gene expression was dependent on activation of ERK1/2, while increases in IL-12p40, iNOS, and IL-10 gene expression were dependent on activation of p38. Because early activation of p38 was unimpaired in MAP-infected macrophages, we propose that MAP interferes with gene expression of iNOS and IL-12p40 genes downstream of p38.
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PMID:Mycobacterium avium subspecies paratuberculosis suppresses expression of IL-12p40 and iNOS genes induced by signalling through CD40 in bovine monocyte-derived macrophages. 1902 5

Glutamine (Gln) and arginine (Arg) are conditionally essential amino acids with immunomodulatory properties. The aim of the study was to assess the effects of Gln and Arg alone or in combination on cytokine release by cultured colonic biopsies from patients with active Crohn's disease (CD). Ten consecutive patients [mean (range) age 26 (18-39) y] with active colonic CD (mean CD activity index: 383.7 +/- 129.8) were prospectively included in the study. Eight colonic biopsies were obtained via a colonoscopy and incubated during 18 h with low (physiological) or high (pharmacological) doses of Arg (0.1 or 2 mmol/L designated as Arg(low) or Arg(high), respectively) and Gln (0.6 or 10 mmol/L designated as Gln(low) or Gln(high), respectively). The concentrations of cytokines [interleukin (IL)-4, IL-10, IL-8, IL-6, tumor necrosis factor-alpha (TNFalpha), IL-1beta, interferon-gamma) were assessed by ELISA, and nitric oxide (NO) production was evaluated by Griess assay. Nuclear factor (NF)-kappaB p65 subunit, inhibitor of NFkappaB-alpha, and p38 mitogen-activated protein kinase (MAPK) were assessed by immunoblotting. Arg(high)/Gln(high) decreased the production of TNFalpha, IL-1beta, IL-8, and IL-6 (each P < 0.01). Arg(low)/Gln(high) decreased IL-6 and IL-8 production (both P < 0.01), whereas Arg(high)/Gln(low) did not affect cytokine and NO production. Arg(low)/Gln(high) and Arg(high)/Gln(high) decreased NF-kappaB p65 subunit expression, whereas p38 MAPK was decreased only by Arg(high)/Gln(high). Combined pharmacological doses of Arg and Gln decreased TNFalpha and the main proinflammatory cytokines release in active colonic CD biopsies via NF-kappaB and p38 MAPK pathways. These results could be the basis of prospective studies evaluating the effects of enteral supply of combined Arg and Gln during active CD.
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PMID:Combined glutamine and arginine decrease proinflammatory cytokine production by biopsies from Crohn's patients in association with changes in nuclear factor-kappaB and p38 mitogen-activated protein kinase pathways. 1902 76


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