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)

Cytokines are a large family of small proteins secreted by leukocytes and having an essential role in mediating the immune function. Many cytokines have multiple cellular sources and targets, as well as many natural inducers and inhibitors. These features and moreover the functional particularities of cytokines (autocrine and paracrine mode of action, overlapped activities, pleiotropic action, functioning as a complex regulatory network, and reciprocal down-regulation of the Th1 and Th2 cytokine groups) hampered the investigation of cytokines' role in autoimmune diseases (ADs). Despite this, the experimental and clinical studies have firmly documented the implication of cytokines in major pathophysiological and pathogenetic mechanisms associated with both the acute (onset and/or recurrence) and the chronic stages of ADs. The enhanced production of cytokines during the acute phase of systemic lupus erythematosus, rheumatoid arthritis and vasculitis has pathogenic effects such as appearance of anti-neutrophil cytoplasmic antibodies, initiation of vascular thrombosis and/or an increased production of autoantigens. The potent proinflammatory cytokines IL-1 and TNFalpha and also IL-8 and IFNalpha,gamma stimulate cells in different tissues to release harmful proteinases and reactive oxygen species, contributing to tissue damage. Some correlations have been found between serum cytokine levels and disease activity in certain systemic ADs. Studies investigating the cytokine pattern in ADs revealed the prevalence of the proinflammatory Th1-type cytokines in the target organ of patients with organ-specific ADs, such as multiple sclerosis and autoimmune thyroid disease, and heterogeneous cytokine profiles in patients with systemic ADs. A lot of factors, including the mechanism of tissue damage, the type of antigen-presenting cells and costimulatory molecules, and also the hormonal status, favor secretion of cytokines of Th1- or Th2-type in these patients. Beneficial effects have been obtained in patients with rheumatoid arthritis and Crohn disease by administering biotechnologically manufactured anti-TNFalpha antibodies or TNFalpha receptors. The risks of these cytokine-targeting therapeutical interventions are also discussed.
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PMID:Cytokine patterns and pathogenicity in autoimmune diseases. 1552 38

Inflammatory and/or autoimmune diseases like ulcerative colitis (UC) or Crohn's disease (CD) are debilitating chronic disorders that poorly respond to pharmacological interventions. Further, drug therapy has adverse effects that add to disease complications. The current thinking is that disorders like inflammatory bowel disease (IBD) reflect an over exuberant immune activation driven by cytokines including TNF-alpha. Major sources of cytokines include myeloid leukocytes (granulocytes, monocytes/macrophages), which in IBD are elevated with activation behavior and are found in vast numbers within the inflamed intestinal mucosa. Accordingly, myeloid cells should be the targets of therapy. Adacolumn is filled with cellulose acetate beads that selectively adsorb and deplete myeloid cells and a small fraction of lymphocytes (FcgammaR and complement receptors bearing cells). In one study, 20 steroid naive patients with moderate (n = 14) or severe (n = 6) UC according to Rachmilewitz despite 1.5-2.25 g/day of 5-aminosalicylic acid received 6 to 10 Adacolumn sessions at 2 sessions/week. Efficacy was assessed 1 week after the last session. The majority of patients responded to 6 sessions, 17 (85%) achieved remission. In 2 of the 3 non-responders, CAI was 8 and 12 in 1; all 3 had deep colonic ulcers at study initiation. Decreases were seen in total leukocytes (P = 0.003), % neutrophils (P = 0.003), % monocytes (P = 0.004), an increase in lymphocytes (P = 0.001), decreases in C-reactive protein (P = 0.0002), and rises in blood levels of soluble TNF-alpha receptors I (P = 0.0007), II (P = 0.0045). In a separate study, a case with very severe steroid refractory UC who received up to 11 sessions responded well and avoided colectomy. Further, myeloid cell purging with Adacolumn has been associated with the release of IL-1 receptor antagonist, suppression of TNF-alpha, IL-1beta, IL-6, IL-8, down-modulation of L-selectin and the chemokine receptor CXCR3. In conclusion, selective depletion of myeloid cells appears to induce anti-inflammatory effects and represents a non-pharmacological treatment for patients with active IBD. The treatment has a clear drug-sparing role. Changes in blood levels of inflammatory and anti-inflammatory factors are thought to contribute to the efficacy of this procedure.
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PMID:Adacolumn for selective leukocytapheresis as a non-pharmacological treatment for patients with disorders of the immune system: an adjunct or an alternative to drug therapy? 1610 51

Both NOD2 (CARD15) alleles are mutated in roughly 15% of patients with Crohn's disease, but functional effects are unclear. We analysed the cytokine response of peripheral blood mononuclear cells to muramyl dipeptide (MDP), the ligand for NOD2. MDP induced little TNFalpha or interleukin 1beta, but strong interleukin-8 secretion. MDP also substantially upregulated secretion of TNFalpha and interleukin 1beta induced by toll-like receptor ligands. These effects were abolished by the most common Crohn's NOD2 double mutant genotypes at low nanomolar MDP concentrations, and provide the basis to develop a test of NOD2 functional deficiency. In Crohn's disease, there are defects in neutrophil recruitment driven by NOD2 and interleukin 8 and in cross talk between the NOD2 and toll-like receptor pathways, which suggests that the immune system fails to receive an early priming signal.
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PMID:Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. 1591 Sep 38

Recognition of repeat CpG motifs, which are common in bacterial, but not in mammalian, DNA, through Toll-like receptor (TLR)9 is an integral part of the innate immune system. As the role of TLR9 in the human gut is unknown, we determined the spectrum of TLR9 expression in normal and inflamed colon and examined how epithelial cells respond to specific TLR9 ligand stimulation. TLR9 expression was measured in human colonic mucosal biopsies, freshly isolated human colonic epithelial cells and HT-29 cells by reverse transcriptase-polymerase chain reaction or Western blotting. Colonic epithelial cell cultures were stimulated with a synthetic CpG-oligodeoxynucleotide (ODN), exhibiting strong immunostimulatory effects in B cells. Interleukin (IL)-8 secretion was determined by enzyme-linked immunosorbent assay, nuclear factor-kappaB (NF-kB) activity by electrophoretic mobility shift assay and IkB phosphorylation by Western blotting. TLR9 mRNA was equally expressed in colonic mucosa from controls (n = 6) and patients with ulcerative colitis or Crohn's disease disease (n = 13). HT-29 cells expressed TLR9 mRNA and protein and responded to CpG-ODN (P < 0.01), but not to non-CpG-ODN stimulation, by secreting IL-8, apparently in the absence of NF-kB activation. Primary epithelial cells isolated from normal human colon expressed TLR9 mRNA, but were completely unresponsive to CpG-ODN stimulation in vitro. In conclusion, differentiated human colonic epithelial cells are unresponsive to TLR9 ligand stimulation in vitro despite spontaneous TLR9 gene expression. This suggests that the human epithelium is able to avoid inappropriate immune responses to luminal bacterial products through modulation of the TLR9 pathway.
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PMID:Expression of Toll-like receptor 9 and response to bacterial CpG oligodeoxynucleotides in human intestinal epithelium. 1599 94

The expression of CCL20 (MIP-3alpha), which chemoattracts leukocytes to sites of inflammation, has been shown in intestinal epithelial cells (IEC). Aim of this study was to analyze the role of the CCL20 receptor CCR6 in IEC and colorectal cancer (CRC) cells. Expression of CCR6 and CCL20 was analyzed by RT-PCR and immunohistochemistry. Signaling was investigated by Western blotting, proliferation by MTS assays and chemotactic cell migration by wounding assays. The effect of CCL20 on Fas-induced apoptosis was determined by flow cytometry. CCR6 and its ligand CCL20 are expressed in IEC. Moreover, CRC and CRC metastases express CCR6, which is upregulated during IEC differentiation. Stimulation of IEC with CCL20 and proinflammatory stimuli (TNF-alpha, IL-1beta, LPS) significantly upregulates CCL20 mRNA expression. CCL20 expression was significantly increased in inflamed colonic lesions in Crohn's disease and correlated significantly with the IL-8 mRNA expression in these lesions (r = 0.71) but was downregulated in CRC metastases. CCL20 activated Akt, ERK-1/2, and SAPK/JNK MAP kinases and increased IL-8 protein expression. The CCL20 mediated activation of these pathways resulted in a 2.6-fold increase of cell migration (P = 0.001) and in a significant increase of cell proliferation (P < 0.05) but did not influence Fas-induced apoptosis. In conclusion, IEC and CRC express CCL20 and its receptor CCR6. CCL20 expression is increased in intestinal inflammation, while CCR6 is upregulated during cell differentiation. CCR6 mediated signals result in increased IEC migration and proliferation suggesting an important role in intestinal homeostasis and intestinal inflammation by mediating chemotaxis of IEC but also in mediating migration of CRC cells.
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PMID:Cell differentiation dependent expressed CCR6 mediates ERK-1/2, SAPK/JNK, and Akt signaling resulting in proliferation and migration of colorectal cancer cells. 1621 92

A major mechanism for apical peptide absorption by small intestine is via the proton-coupled transporter PepT1. PepT1 is expressed at a high level in proximal small intestine, but it is not expressed in the healthy colon. However, in chronic states of intestinal inflammation, such as in Crohn's disease and ulcerative colitis, PepT1 expression in colonic epithelia is increased, serving as a pathway for entry of bacteria-derived molecules such as muramyl dipeptide (MDP) and fMet-Leu-Phe (fMLP). As little is known of how inflammation induces PepT1, we investigated whether or not inflammatory cytokines and mediators such as interleukins (IL)-1beta, IL-2, IL-8, IL-10, tumor necrosis factor-alpha, (TNF-alpha) and interferon-gamma (IFN-gamma ) up-regulate PepT1 activity and expression. Uptake of the PepT1 substrate glycylsarcosine [(3)H]-Gly-Sar was studied in vitro in the human colon carcinoma cell line Caco2/bbe monolayers as well as in vivo in mice injected with cytokines. TNF-alpha and IFN-gamma increased the activity, and total and apical membrane protein expression of PepT1 protein in a concentration- and time-dependent fashion. No changes in PepT1 mRNA were observed, suggesting post-transcriptional regulation. All three cytokines increased PepT1 protein expression in mouse proximal and distal colon but not in jejunum or ileum. TNF-alpha and IFN-gamma, but not IL-1beta, increased Gly-Sar uptake in mouse proximal and distal colon; however, no changes were observed in the small intestine with any cytokine treatment. Whereas neither TNF-alpha nor IFN-gamma increased PepT1 mRNA expression in any segment of the intestine, treatment with IL-1beta increased PepT1 mRNA expression in mouse proximal and distal colon and decreased PepT1 mRNA expression in jejunum and ileum. Since PepT1 transports bacteria-derived peptides, the up-regulation of protein expression and activity observed after treatment with TNF-alpha or IFN-gamma may play a role in activating host responses in involved colon.
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PMID:Tumor necrosis factor-alpha and interferon-gamma increase PepT1 expression and activity in the human colon carcinoma cell line Caco-2/bbe and in mouse intestine. 1632 52

Duodenal Crohn's disease is rare, and patients without obstruction are treated medically. We herein report one case whose duodenal Crohn's disease was successfully managed with low-speed elemental diet infusion through a nasogastric tube. A 28-year-old female developed acute duodenal Crohn's disease. Upper GI radiologic and endoscopic examinations showed a stricture in the duodenal bulb. Using the duodenal biopsy specimens, mucosal cytokine levels were measured; interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor-alpha levels were remarkably elevated. For initial 2 wk, powdered mesalazine was orally given but it was not effective. For the next 2 wk, she was treated with low-speed elemental diet therapy using a commercially available Elental(TM), which was infused continuously through a nasogastric tube using an infusion pump. The tip of the nasogastric tube was placed at an immediate oral side of the pylorus. The infusion speed was 10 mL/h (usual speed, 100 mL/h). After the 2-wk treatment, her symptoms were very much improved, and endoscopically, the duodenal stricture and inflammation improved. The duodenal mucosal cytokine levels remarkably decreased compared with those before the treatment. Although our experience was limited, low-speed elemental diet infusion through a nasogastric tube may be a useful treatment for acute duodenal Crohn's disease.
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PMID:Acute duodenal Crohn's disease successfully managed with low-speed elemental diet infusion via nasogastric tube: a case report. 1648 85

IL-22 is produced by activated T cells and signals through a receptor complex consisting of IL-22R1 and IL-10R2. The aim of this study was to analyze IL-22 receptor expression, signal transduction, and specific biological functions of this cytokine system in intestinal epithelial cells (IEC). Expression studies were performed by RT-PCR. Signal transduction was analyzed by Western blot experiments, cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and Fas-induced apoptosis by flow cytometry. IEC migration was studied in wounding assays. The IEC lines Caco-2, DLD-1, SW480, HCT116, and HT-29 express both IL-22 receptor subunits IL-22R1 and IL-10R2. Stimulation with TNF-alpha, IL-1beta, and LPS significantly upregulated IL-22R1 without affecting IL-10R2 mRNA expression. IL-22 binding to its receptor complex activates STAT1/3, Akt, ERK1/2, and SAPK/JNK MAP kinases. IL-22 significantly increased cell proliferation (P = 0.002) and phosphatidylinsitol 3-kinase-dependent IEC cell migration (P < 0.00001) as well as mRNA expression of TNF-alpha, IL-8, and human beta-defensin-2. IL-22 had no effect on Fas-induced apoptosis. IL-22 mRNA expression was increased in inflamed colonic lesions of patients with Crohn's disease and correlated highly with the IL-8 expression in these lesions (r = 0.840). Moreover, IL-22 expression was increased in murine dextran sulfate sodium-induced colitis. IEC express functional receptors for IL-22, which increases the expression of proinflammatory cytokines and promotes the innate immune response by increased defensin expression. Moreover, our data indicate intestinal barrier functions for this cytokine-promoting IEC migration, which suggests an important function in intestinal inflammation and wound healing. IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and IEC migration.
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PMID:IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. 1653 74

Both NOD2/CARD15 alleles are mutated in approximately 10% of Crohn's disease patients, causing loss of functional responses to low-dose muropeptide agonists. We hypothesized that NOD2 mutations may also impair NOD1/CARD4 responses, supported by data suggesting NOD2 1007fs/1007fs patients had reduced responses to a putative NOD1 agonist, diaminopimelic acid-containing muramyl tripeptide (M-TriDAP). We measured peripheral blood mononuclear cell (n = 8 NOD2 wild type, n = 4 1007fs/1007fs, n = 6 702Trp/1007fs, n = 5 702Trp/702Trp, n = 3 908Arg/1007fs) responses to NOD1 agonists alone (IL-8/TNF-alpha), and agonist enhancement of lipopolysaccharide (LPS) responses (IL-1beta). Significant responses were seen with M-TriDAP at 10 nM (as with NOD2 agonists), but only at > or =100 nM with FK565/TriDAP. M-TriDAP induced IL-8/TNF-alpha secretion, and enhancement of LPS IL-1beta responses was significantly reduced between NOD2 double mutation carriers versus healthy controls, whereas there was no difference with FK565 or TriDAP stimulation, or between 1007fs/1007fs cells and other genotypes. M-TriDAP contains both NOD1 (gamma-D-Glu-mesoDAP) and NOD2 (MurNAc-L-Ala-D-Glu) minimal structures whereas FK565/TriDAP contain only NOD1 activating structures. M-TriDAP has dual NOD1/NOD2 agonist activity in primary cells, possibly due to different intracellular peptidoglycan processing compared to the HEK293 cell system typically used for agonist specificity studies. Responses to specific NOD1 agonists are unaffected by NOD2 genotype, suggesting independent action of the NOD1 and NOD2 pathways.
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PMID:Normal responses to specific NOD1-activating peptidoglycan agonists in the presence of the NOD2 frameshift and other mutations in Crohn's disease. 1701 77

Expression of the caspase-activating adaptor ASC was reported to be associated with the production of IL-8, a primary mediator of mucosal inflammation, in vitro. However, the significance of the ASC-mediated IL-8 production in primary tissues has remained poorly understood. Primary intestinal mucosa isolated from surgically resected ileum or colon was incubated with several concentrations of LPS or left untreated. ASC expression was up-regulated at 2 h after stimulation with low doses of LPS (1-10 ng/ml), and was associated with IL-8 secretion, and then was down-regulated later. In contrast, ASC expression remained at the basal level in mucosal tissue treated with a high dose of LPS (1000 ng/ml). Interestingly, in mucosa from several cases of Crohn's disease, ASC was highly expressed without stimulation, and IL-8 was stably secreted with no regulation by LPS. These findings revealed that ASC expression correlates with IL-8 secretion and may play an important role in maintaining mucosal homeostasis.
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PMID:Regulation of the ASC expression in response to LPS stimulation is related to IL-8 secretion in the human intestinal mucosa. 1677 61


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