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

To elucidate the pathogenetic mechanism of renal parenchymal injury in autosomal dominant polycystic kidney disease (ADPKD) patients, typically characterized by renal cystic changes paralleled by interstitial inflammation and gradual fibrotic changes, the role of selected inflammatory mediators was evaluated in a group of ADPKD patients with normal glomerular filtration rate. The plasma concentrations of IL-6, IL-8, ICAM-1 and VCAM-1 (which may reflect systemic response to inflammation/infection) were increased in the ADPKD patient group. Coupled with decreased urinary excretion of the IL-1 receptor antagonist (which exerts an anti-inflammatory role), these results suggest that even in overt infection free status, the proinflammatory system is more activated and anti-inflammatory defence system weakened in ADPKD subjects. Our data support the current view that cytokines are candidate contributors to pathogenesis of ADPKD.
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PMID:Cytokine profile in autosomal dominant polycystic kidney disease. 909 Apr 70

The principal extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD) involves formation of liver cysts derived from intrahepatic bile ducts. Autocrine and paracrine factors secreted into the cyst would be positioned to modulate the rate of hepatic cyst growth. The aim of this study was to identify potential growth factors present in human ADPKD liver cyst fluid. Cytokine array and enzyme-linked immunosorbent assay analysis of human ADPKD liver cyst fluid detected epithelial neutrophil attractant 78, interleukin (IL)-6 (503 +/- 121 pg/mL); and IL-8 (4,488 +/- 355 pg/mL); and elevated levels of vascular endothelial growth factor compared with non-ADPKD bile (849 +/- 144 pg/mL vs. 270 pg/mL maximum concentration). ADPKD liver cyst cell cultures also released IL-8 and vascular endothelial growth factor, suggesting that cystic epithelial cells themselves are capable of secreting these factors. Western blotting of cultured cyst cells and immunostaining of intact cysts demonstrate that cysteine-X-cysteine receptor 2, an epithelial neutrophil attractant 78 and IL-8 receptor, is expressed at the apical domain of cyst lining epithelial cells. Suggesting the cystic epithelial cells may exist in hypoxic conditions, electron microscopy of the ADPKD liver cyst epithelium revealed morphological features similar to those observed in ischemic bile ducts. These features include elongation, altered structure, and diminished abundance of apical microvilli. In conclusion, IL-8, epithelial neutrophil attractant 78, IL-6, and vascular endothelial growth factor may serve as autocrine and paracrine factors to direct errant growth of ADPKD liver cyst epithelia. Interruption of these signaling pathways may provide therapeutic targets for inhibiting liver cyst expansion.
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PMID:Secretion of cytokines and growth factors into autosomal dominant polycystic kidney disease liver cyst fluid. 1538 15

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

The signaling pathways mediating lysophosphatidic acid (LPA)-stimulated PKD(2) activation and the potential contribution of PKD(2) in regulating LPA-induced interleukin 8 (IL-8) secretion in nontransformed, human colonic epithelial NCM460 cells were examined. Treatment of serum-deprived NCM460 cells with LPA led to a rapid and striking activation of PKD(2), as measured by in vitro kinase assay and phosphorylation at the activation loop (Ser706/710) and autophosphorylation site (Ser876). PKD(2) activation induced by LPA was abrogated by preincubation with selective PKC inhibitors GF-I and Ro-31-8220 in a dose-dependent manner. These inhibitors did not have any direct inhibitory effect on PKD(2) activity. LPA induced a striking increase in IL-8 production and stimulated NF-kappaB activation, as measured by NF-kappaB-DNA binding, NF-kappaB-driven luciferase reporter activity, and IkappaBalpha phosphorylation. PKD(2) gene silencing utilizing small interfering RNAs targeting distinct PKD(2) sequences dramatically reduced LPA-stimulated NF-kappaB promoter activity and IL-8 production. PKD(2) activation is a novel early event in the biological action of LPA and mediates LPA-stimulated IL-8 secretion in NCM460 cells through a NF-kappaB-dependent pathway. Our results demonstrate, for the first time, the involvement of a member of the PKD family in the production of IL-8, a potent proinflammatory chemokine, by epithelial cells.
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PMID:Protein kinase D2 mediates lysophosphatidic acid-induced interleukin 8 production in nontransformed human colonic epithelial cells through NF-kappaB. 1692 71

The Mxi1 proteins are biochemical and biological antagonists of c-myc oncoprotein. It has been reported that the overexpression pattern of c-myc might be similar to a molecular feature of early and late stages of human autosomal dominant polycystic kidney disease. We identified the cyst phenotype in Mxi1-deficient mice aged 6-12 months using H&E staining. Some chemokines containing a protein domain similar to human IL-8, which is associated with the inflammatory response, were subsequently selected from the up-regulated genes. We confirmed the expression level of these chemokines and measured protein concentrations of IL-8 using ELISA in the Mxi1-knockdown cells. IL-8 was found to be significantly increased in Mxi1-knockdown cells. We found that p38 MAP kinase activation was involved in the signal transduction of the Mxi1-inactivated secretion of IL-8. Therefore, we could suggest that the inactivation of Mxi1 leads to the inflammatory response and has the potential to induce polycystic renal disease.
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PMID:Inactivation of Mxi1 induces Il-8 secretion activation in polycystic kidney. 1735 May 92

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases. Novel molecularly targeted therapies are urgently needed. Here, we extended our studies on the role of protein kinase D1 (PKD1) in PDAC cell lines. Given that Panc-1 express moderate levels of PKD1, we used retroviral-mediated gene transfer to create a Panc-1 derivative that stably over-expresses PKD1 (Panc-1-PKD1). Reciprocally, we used shRNA targeting PKD1 in Panc-28 to produce a PKD1 under-expressing Panc-28 derivative (Panc-28-shPKD1). Our results demonstrate that Panc-1-PKD1 cells exhibit significantly increased anchorage-independent growth in soft agar and increased in vitro invasion compared with Panc-1-mock. Reciprocally, Panc-28-shPKD1 cells show a significant decrease in anchorage-independent growth and invasiveness, as compared with Panc-28-mock cells. The selective PKD family inhibitor CRT0066101 markedly decreased colony-forming ability and invasiveness by either Panc-1-PKD1 or Panc-28-mock cells. Secretion of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and CXC chemokines (CXCL8) was significantly elevated by PKD1 over-expression in Panc-1 cells and reduced either by depletion of PKD1 via shRNA in Panc-28 cells or by addition of CRT0066101 to either Panc-1-PKD1 or Panc-28-mock cells. Furthermore, human umbilical vein endothelial cell (HUVEC) tube formation was significantly enhanced by co-culture with Panc-1-PKD1 compared with Panc-1-mock in an angiogenesis assay in vitro. Conversely, PKD1 depletion in Panc-28 cells decreased their ability to induce endotube formation by HUVECs. PDAC-induced angiogenesis in vitro and in vivo was markedly inhibited by CRT0066101. Our results lend further support to the hypothesis that PKD family members provide a novel target for PDAC therapy.
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PMID:Protein kinase D1 promotes anchorage-independent growth, invasion, and angiogenesis by human pancreatic cancer cells. 2085 18