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)

Acute appendicitis (AA) is the most common life-threatening surgical emergency in pediatrics. To characterize the nature of the inflammatory response in AA, gene expression profiles were generated. We found remarkable uniformity in the genes that were differentially expressed between patients with appendicitis and control groups. Sixty-four probe sets were differentially expressed in samples from patients with both severe and mild appendicitis compared to control samples, and within this group we were able to identify four dominant clusters. Interestingly, expression levels of interleukin (IL)-8 significantly correlated with histologic score, and expression of IL-8 protein was observed within both neutrophils and mononuclear cells by immunohistochemistry, suggesting a possible role in the etiology of appendicitis. Although there was some overlap between genes reported to be differentially expressed in Crohn's disease (CD) and those observed in AA, differential expression of genes involved in interferon responses that characterize CD was not observed.
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PMID:Acute appendicitis is characterized by a uniform and highly selective pattern of inflammatory gene expression. 1907 91

In an effort to develop a molecular classification scheme for Crohn's disease (CD), mucosal biopsies from 69 CD patients and 28 normal controls were analyzed for expression of the RelA subunit of nuclear factor (NF)-kappaB, A20 (a negative regulator of NF-kappaB), polymeric immunoglobulin receptor (pIgR), tumor necrosis factor (TNF), and interleukin (IL)-8. Principal component analysis was used to classify individuals into three subsets based on patterns of biomarker expression. Set 1 included normal subjects and CD patients with mild disease and good responses to therapy, thus defining "normal" biomarker expression. CD patients in set 2, characterized by low expression of all five biomarkers, had moderate to severe disease and poor responses to immunosuppressive and anti-TNF therapy. Patients in set 3, characterized by low expression of RelA, A20, and pIgR, normal TNF and elevated IL-8, had acute inflammation that responded well to therapy. Classification of CD patients by these biomarkers may predict disease behavior and responses to therapy.
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PMID:Signature biomarkers in Crohn's disease: toward a molecular classification. 1907 4

Goblet cells are mucin-secreting intestinal cells forming the mucus layer that protects the mucosal surface. Ulcerative colitis (UC) has been associated with a defective colonic mucus layer and a reduced number of goblet cells. In experimental animals, colonic goblet cell differentiation is regulated by interacting transcription factors Hath1, KLF4 and the Notch, as well as Wnt pathways, whereas data in humans are limited. We investigated goblet cell differentiation factors and mucins in controls and in inflammatory bowel diseases (IBDs). We performed real-time PCR for Hath1, KLF4, several ligands, receptors and target genes of the Notch and Wnt pathways, as well as several mucins in biopsies from the sigmoid colon of controls (n=21), Crohn's disease (CD, n=48) and UC (n=40). In addition, Hath1 protein was quantitated with Western blot and localized with immunohistochemistry. Notably, the degree of inflammation as measured by IL-8 and histology was similar in both disease entities. The proportion of goblet cells was lowered in both IBDs, but specifically diminished in the upper third of the crypt in UC. Comparable levels of inflammation induced both Hath1 (2.0-fold, p<0.001) and KLF4 (1.8-fold for KLF4, p=0.031) mRNA expression in CD but not in UC (0.8-0.9-fold, ns). The differential induction was confirmed for Hath1 protein using Western blot. Hath1 immunostaining was found mostly in the lower half of the colonic crypts. Hath1, KLF4 and the Notch target gene Hes1 were significantly (p<0.001) and positively correlated. Moreover, both Hath1 and KLF4 were correlated (p<0.001) with MUC1, MUC2 as well as MUC4 in all control and IBD cohorts. The results indicate that both transcription factors are key regulators of goblet cell differentiation and mucin formation in the human colon. Conspicuously, inflammation is associated with an enhanced goblet cell differentiation in CD but not in UC, a defect possibly of pathogenic importance.
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PMID:Differences in goblet cell differentiation between Crohn's disease and ulcerative colitis. 1928 67

Ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis are defined as inflammatory bowel diseases (IBD). Those diseases involve disorders of numerous immunological mechanisms associated with cellular and humoral immune response. In CD cellular response is considered to be of crucial importance, and dominant cytokines include: tumor necrosis factor alpha (TNF-alpha), interferon gamma (INF-gamma) and interleukins 1beta (IL-1beta), IL-2, IL-6, IL-8, IL-12. In UC, increased expression of Th2 (responsible for humoral response) is observed. It is connected with increased production of interleukins: 4 (IL-4), IL-5, IL-6, IL-10 and TNF-alpha. Lack of balance between pro-inflammatory and anti-inflammatory cytokines is of vital importance in pathogenesis of IBD. Conventional therapy of CD and UC quite commonly fails to bring satisfactory results, therefore an interest in new therapeutic options, that is, biological therapy, gene therapy, hematopoietic stem cell transplantation, and leucapheresis, has aroused recently. Biological therapy is focused on different stages of the inflammatory process. The fundamentals of biological strategy involve neutralization of pro-inflammatory cytokines, use of anti-inflammatory cytokines and inhibition of neutrophil adhesion. Biological therapy is a promising option because it enables to withdraw corticosteroids and immunosuppressive agents or to reduce their dose. Moreover, it shortens the hospital stay, allows to avoid surgical procedures, extends the remission period and improves patients' quality of life. Currently, 2 agents, infliximab and adalimumab, are registered for the biological therapy of CD in Poland.
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PMID:Biological therapy of inflammatory bowel disease. 1934 Nov 84

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic mucosal injury and the infiltration of inflammatory cells. Tumor suppressor FOXO3 regulates gene expression and its translocation to the cytosol leads to the abrogation of its transcriptional function. We have previously shown that bacterial infection regulates FOXO3 in intestinal epithelial cells and increases cytokine levels. As TNFalpha is a major contributor in intestinal inflammation, the aim of this study was to assess its effect on FOXO3 and FOXO3's contribution to intestinal inflammation in vitro and in vivo. TNFalpha induces the translocation of nuclear FOXO3 into the cytosol where it undergoes proteasomal degradation in human intestinal HT-29 cells. Proximally, the PI3K and IKK pathways mediate TNFalpha-induced FOXO3 phosphorylation. In FOXO3-silenced HT-29 cells, TNFalpha-induced IL-8 expression is increased approximately 83%. In vivo, Foxo3 is present in the nuclei and cytosol of colonic crypt epithelia. In DSS-induced colonic inflammation, Foxo3's nuclear localization is lost and it is only found in the cytosol. Consistent with a role for Foxo3 in colitis, Foxo3-deficient mice treated with DSS developed more severe colonic inflammation with an increased number of intraepithelial lymphocytes and PMNs infiltrated in the epithelia, than wild-type mice. In summary, TNFalpha inactivates FOXO3 in intestinal epithelia through the PI3K and IKK pathways and FOXO3 inactivation leads to the upregulation of IL-8 in vitro; in vivo Foxo3 is in the cytosol of inflamed colonic epithelia and Foxo3 deficiency leads to severe intestinal inflammation.
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PMID:Tumor suppressor FOXO3 participates in the regulation of intestinal inflammation. 1963 95

The endocannabinoid system is an ancient lipid signaling network which in mammals modulates neuronal functions, inflammatory processes, and is involved in the aetiology of certain human lifestyle diseases, such as Crohn's disease, atherosclerosis and osteoarthritis. The system is able to downregulate stress-related signals that lead to chronic inflammation and certain types of pain, but it is also involved in causing inflammation-associated symptoms, depending on the physiological context. The cannabinoid type-2 (CB(2)) receptor, which unlike the CB(1) receptor does not induce central side effects, has been shown to be a promising therapeutic target. While CB(1) receptor antagonists/inverse agonists are of therapeutic value, also CB(2) receptor ligands including agonists are of pharmacological interest. Although the endocannabinoid system is known to be involved in the regulation of energy homoeostasis and metabolism (mainly via CB(1) receptors) there was hitherto no direct link between food intake and cannabinoid receptor activation. Our recent finding that beta-caryophyllene, a ubiquitous lipohilic plant natural product, selectively binds to the CB(2) receptor and acts as a full agonist is unexpected. Maybe even more unexpected is that oral administration of this dietary compound exerts potent anti-inflammatory effects in wild type mice but not in CB(2) receptor (Cnr2(-/-)) knockout mice. Like other CB(2) ligands also beta-caryophyllene inhibits the pathways triggered by activation of the toll-like receptor complex CD14/TLR4/MD2, which typically lead to the expression of proinflammatory cytokines (IL-1beta, IL-6; IL-8 and TNFalpha) and promotes a TH(1) immune response. In this addendum, the CB(2) receptor-dependent effect of beta-caryophyllene on LPS-triggered activation of the kinases Erk1/2 and JNK1/2 are further discussed with respect to the possibility that both CB(2) inverse agonists and agonists, independent of their G-protein signaling, may block LPS-triggered activation of MAPKs, leading to inhibition of proinflammatory cytokine expression and attenuation of inflammation.
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PMID:Anti-inflammatory cannabinoids in diet: Towards a better understanding of CB(2) receptor action? 1970 83

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology. The main pathological feature of IBD is transmural infiltration of polymorphonuclear neutrophils (PMN) and mononuclear cells associated with smooth muscle cell proliferation, accumulation of collagen, thickening and stenosis. While the etiology of Crohn's disease remains unknown, increased levels of proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF in the inflamed bowel probably play a major role in the tissue injury and fibrosis that ensue. PMNs infiltrate into tissue in response to chemotactic signals produced by the tissue, such as a-chemokines (IL-8). Although, the initial infiltration of neutrophils is beneficial to kill foreign particles and bacteria, persistent infiltration causes tissue damage. This review shows some evidence of neutrophil expression in Crohn's bowel and the process of neutrophil infiltration into the inflamed tissue.
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PMID:Neutrophil expression and infiltration into Crohn's intestine. 1986 48

Interleukin-17A (IL-17A) and IL-17F are 2 of several cytokines produced by T helper 17 cells (Th17), which are able to indirectly induce the recruitment of neutrophils. Recently, human Th17 cells have been phenotypically characterized and shown to express discrete chemokine receptors, including CCR2 and CCR6. Herein, we show that highly purified neutrophils cultured with interferon-gamma plus lipopolysaccharide produce the CCL2 and CCL20 chemokines, the known ligands of CCR2 and CCR6, respectively. Accordingly, supernatants from activated neutrophils induced chemotaxis of Th17 cells, which was greatly suppressed by anti-CCL20 and anti-CCL2 antibodies. We also discovered that activated Th17 cells could directly chemoattract neutrophils via the release of biologically active CXCL8. Consistent with this reciprocal recruitment, neutrophils and Th17 cells were found in gut tissue from Crohn disease and synovial fluid from rheumatoid arthritis patients. Finally, we report that, although human Th17 cells can directly interact with freshly isolated or preactivated neutrophils via granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and interferon-gamma release, these latter cells cannot be activated by IL-17A and IL-17F, because of their lack of IL-17RC expression. Collectively, our results reveal a novel chemokine-dependent reciprocal cross-talk between neutrophils and Th17 cells, which may represent a useful target for the treatment of chronic inflammatory diseases.
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PMID:Evidence for a cross-talk between human neutrophils and Th17 cells. 1989 92

Inflammatory bowel disease (IBD) is a GI tract disorder that manifests as either Ulcerative colitis (UC) or Crohn's disease (CD). The precise etiology of IBD is still not completely elucidated but research into the immunopathogenesis of IBD suggests that dysfunctions of the intestinal immune system and cross-reactivity against host epithelial cells hold the key. In both UC and CD, polarized immune activity towards Th1 (marked by upregulation of TNF-alpha, IL-1beta, IFN-gamma, IL-6) and Th17 (marked by IL-17 secretion) response is reported, while UC appears to exhibit an added contribution of Th2 responses (characterized by secretion of IL-4, IL-5, and IL-13). Additionally, other molecules involved in leukocyte trafficking (adhesion molecules), chemokines (IL-8) and tissue repair molecules (PGE(2) and its receptors) are also crucial. Emergence of these new paradigms in the pathogenesis of IBD led to a recent trend of novel biological therapies that specifically inhibit molecules involved in the inflammatory cascade. In this review, we critically discuss recent advances in the pathogenesis of IBD, drug therapies (conventional versus biologic), drug efficacy and pharmacokinetics (murine versus human versus chimeric) and their adverse effects. We also discuss emerging novel biological therapies targeting pro-inflammatory cytokines including TNF-alpha and IFN-gamma, cytokine receptors and those targeting adhesion molecules-anti-integrin and anti-ICAM antibodies. Other potential approaches using anti-inflammatory cytokines (IL-10), anti-sense oligonucleotide and probiotics are also discussed. Finally, we summarized few imperative targets whose more detailed exploration can help to pave the way for an efficacious IBD therapy.
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PMID:Biologic therapies against inflammatory bowel disease: a dysregulated immune system and the cross talk with gastrointestinal mucosa hold the key. 2002 34

In inflammatory bowel diseases (IBD), intestinal epithelial cells (IECs) are involved in the outbalanced immune responses toward luminal antigens. However, the signals responsible for this proinflammatory capacity of IECs in IBD remain unclear. The CD40/CD40L interaction activates various pathways in immune and nonimmune cells related to inflammation and was shown to be critical for the development of IBD. Here we demonstrate CD40 expression within IECs during active IBD. Endoscopically obtained biopsies taken from Crohn's disease (n = 112) and ulcerative colitis patients (n = 67) consistently showed immunofluorescence staining for CD40 in IECs of inflamed ileal or colonic mucosa. In noninvolved mucosa during active disease, tissue obtained during Crohn's disease or ulcerative colitis in remission and biopsies from healthy controls (n = 38) IECs almost entirely lacked CD40 staining. Flow cytometry and RT-PCR analysis using different intestinal epithelial cell lines (HT29, SW480, and T84) showed IFN-gamma to effectively induce CD40 in IECs. Cells were virtually unresponsive to LPS or whole E. coli regarding CD40 expression. In addition, a moderate induction of CD40 was found in response to TNF-alpha, which exerted synergistical effects with IFN-gamma. CD40 ligation by CD40L-transfected murine fibroblasts or soluble CD40L increased the secretion of IL-8 in IFN-gamma pretreated HT29 cells. Our findings provide evidence for the epithelial expression and modulation of CD40 in IBD-affected mucosa and indicate its involvement in the proinflammatory function of IECs.
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PMID:The CD40-CD40L pathway contributes to the proinflammatory function of intestinal epithelial cells in inflammatory bowel disease. 2013 13


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