Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pro-inflammatory mediators formed by the kallikrein-kinin system can stimulate bone resorption and synergistically potentiate bone resorption induced by IL-1 and TNF-alpha. We have shown that the effect is associated with synergistically enhanced RANKL expression and enhanced prostaglandin biosynthesis, due to increased cyclooxygenase-2 expression. In the present study, the effects of osteotropic cytokines and different kinins on the expression of receptor subtypes for bradykinin (BK), des-Arg10-Lys-BK (DALBK), IL-1beta and TNF-alpha have been investigated. IL-1beta and TNF-alpha enhanced kinin B1 and B2 receptor binding in the human osteoblastic cell line MG-63 and the mRNA expression of B1 and B2 receptors in MG-63 cells, human gingival fibroblasts and intact mouse calvarial bones. Kinins did not affect mRNA expression of IL-1 or TNF receptors. EMSA showed that IL-1beta and TNF-alpha activated NF-kappaB and AP-1 in MG-63 cells. IL-1beta stimulated NF-kappaB via a non-canonical pathway (p52/p65) and TNF-alpha via the canonical pathway (p50/p65). Activation of AP-1 involved c-Jun in both IL-1beta and TNF-alpha stimulated cells, but c-Fos only in TNF-alpha stimulated cells. Phospho-ELISA and Western blots showed that IL-1beta activated JNK and p38, but not ERK 1/2 MAP kinase. Pharmacological inhibitors showed that NF-kappaB, p38 and JNK were important for IL-1beta induced stimulation of B1 receptors, and NF-kappaB and p38 for B2 receptors. p38 and JNK were important for TNF-alpha induced stimulation of B1 receptors, whereas NF-kappaB, p38 and JNK were involved in TNF-alpha induced expression of B2 receptors. These data show that IL-1beta and TNF-alpha upregulate B1 and B2 receptor expression by mechanisms involving activation of both NF-kappaB and MAP kinase pathways, but that signal transduction pathways are different for IL-1beta and TNF-alpha. The enhanced kinin receptor expression induced by the pro-inflammatory cytokines IL-1beta and TNF-alpha might be one important mechanism involved in the synergistic enhancement of prostaglandin formation caused by co-treatment with kinins and one of the two cytokines. These mechanisms might help to explain the enhanced bone resorption associated with inflammatory disorders, including periodontitis and rheumatoid arthritis.
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PMID:Kinin B1 and B2 receptor expression in osteoblasts and fibroblasts is enhanced by interleukin-1 and tumour necrosis factor-alpha. Effects dependent on activation of NF-kappaB and MAP kinases. 1846 3

TNFalpha exerts apoptosis throughout an intracellular transduction pathway that involves the kinase proteins TRAF-2 (integration point of apoptotic and survival signals), ASK1 (pro-apoptotic protein), MEK-4 (p38 activator and metastasis suppressor gene), JNK (stress mitogen activated protein kinase) and the transcription factor AP-1. TNFalpha also exerts proliferation by p38 activation, or when TRAF-2 simultaneously induces the transcription factor NF-kappaB by NIK. NIK and p38 may also be activated by IL-1. P38 activated several transcription factors such as Elk-1, ATF-2 and NF-kappaB. NIK also may activate NF-kappaB. The aim of the present article was to evaluate the different components of this TNFalpha/IL-1 transduction pathway in human prostate carcinoma (PC) in comparison with normal human prostate. In prostate cancer, pro-apoptotic TNFalpha/AP-1 pathway is probably inactivated by different factors such as p21 (at ASK-1 level) and bcl-2 (at JNK level), or diverted towards p38 or NIK activation. IL-1alpha enhances proliferation through IL-1RI that activates either NIK or p38 transduction pathway. P38 and NIK activate different transcription factors related with cell proliferation and survival such as ATF-2, Elk-1 or NF-kappaB. In order to search a possible target to cancer prostate treatment we proposed that inhibition of several proinflamatory cytokines such as IL-1 and TNFalpha might be a possible target for PC treatment, because decrease the activity of all transduction pathway members that activate transcription factors as NF-kappaB, Elk-1 or ATF-2.
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PMID:TNF-alpha/IL-1/NF-kappaB transduction pathway in human cancer prostate. 1871 80

Chronic hepatitis C virus (HCV) infection is a major cause of liver fibrosis ultimately leading to cirrhosis. Hepatic stellate cell (HSC) proliferation is crucial in fibrosis development. Current antiviral treatment for HCV involves interferon-alpha (IFN-alpha) and Ribavirin combination therapy. IL-18, a novel cytokine of the IL-1 family of cytokines, is involved in inflammation and may be important in HCV-related inflammation. We hypothesize that block of one of the crucial events will block fibrosis due to HCV. The effect of HCV patient sera with and without IFN-alpha, ribavirin, and IL-18 antibody on HSC proliferation was assessed by [(3)H]-thymidine incorporation assays. Western analysis was used to assess the effect of pentoxifylline (PTX) on c-Jun immediate early gene phosphorylation (p-c-Jun formation). We demonstrate that HCV patient sera-stimulated HSC proliferation. Ribavirin with or without IFN-alpha significantly decreased HCV sera-stimulated HSC proliferation by 50%. Western analysis revealed that HCV serum increased p-c-Jun levels, which were decreased with Ribavirin and PTX. ELISA results showed an elevation of IL-18 levels in HCV sera when compared to normal sera. IL-18 did not stimulate HSC proliferation. However, IL-18 antibody significantly decreased patient sera-stimulated HSC proliferation. In conclusion, Ribavirin decreased HSC proliferation and may act by decreasing p-c-Jun levels in HSCs. IL-18 alone did not stimulate HSC proliferation but IL-18 antibody decreased stimulation, suggesting that IL-18 may work in conjunction with some other factor to increase HSC proliferation.
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PMID:Effect of interferon-alpha, ribavirin, pentoxifylline, and interleukin-18 antibody on hepatitis C sera-stimulated hepatic stellate cell proliferation. 1884 79

Heat shock protein 90 (Hsp90) is an abundantly and ubiquitously expressed chaperone with majority of client proteins which act as signal molecules. Transforming growth factor beta-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK), and is essential in interleukin-1beta (IL-1beta) triggered signaling pathways. In the present study, we found that Hsp90 plays an important role in regulating IL-1beta signaling by keeping TAK1 stability. The results showed that the specific inhibitor geldanamycin (GA) of Hsp90 dramatically inhibited IL-1beta stimulated TAK1-MAPKs and TAK1-nuclear factor-kappaB (NF-kappaB) activation, resulting in the decrease of cyclooxygenase-2 (COX-2) protein expression. Silencing Hsp90 expression through RNA interference (RNAi) also down-regulated TAK1, as well as attenuated IL-1beta induced phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and p38 MAPKs, and degradation of IkappaBalpha. The same results were obtained in T6RZC stable cells which initiated IL-1beta-induced cell signaling at the level of the oligomerization and ubquitination of TNF receptor-associated factor 6 (TRAF6). We further found that Hsp90 formed a complex with TAK1 via its N-terminal domain and GA destabilized TAK1 and induced TAK1 degradation through proteasome pathway. Taken together our results demonstrate that Hsp90 regulates IL-1beta-induced signaling by interacting with TAK1 and maintaining the stability of TAK1, suggesting that Hsp90 might act as the chaperone of TAK1 in immune and inflammatory responses related with IL-1 signal cascades.
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PMID:Heat shock protein 90 (Hsp90) regulates the stability of transforming growth factor beta-activated kinase 1 (TAK1) in interleukin-1beta-induced cell signaling. 1895 Aug 63

Chronic inflammation and inflammatory cytokines have recently been implicated in the development and progression of various types of cancer. In the brain, neuroinflammatory cytokines affect the growth and differentiation of both normal and malignant glial cells, with interleukin 1 (IL-1) shown to be secreted by the majority of glioblastoma cells. Recently, elevated levels of sphingosine kinase 1 (SphK1), but not SphK2, were correlated with a shorter survival prognosis for patients with glioblastoma multiforme. SphK1 is a lipid kinase that produces the pro-growth, anti-apoptotic sphingosine 1-phosphate, which can induce invasion of glioblastoma cells. Here, we show that the expression of IL-1 correlates with the expression of SphK1 in glioblastoma cells, and neutralizing anti-IL-1 antibodies inhibit both the growth and invasion of glioblastoma cells. Furthermore, IL-1 up-regulates SphK1 mRNA levels, protein expression, and activity in both primary human astrocytes and various glioblastoma cell lines; however, it does not affect SphK2 expression. The IL-1-induced SphK1 up-regulation can be blocked by the inhibition of JNK, the overexpression of the dominant-negative c-Jun(TAM67), and the down-regulation of c-Jun expression by small interference RNA. Activation of SphK1 expression by IL-1 occurs on the level of transcription and is mediated via a novel AP-1 element located within the first intron of the sphk1 gene. In summary, our results suggest that SphK1 expression is transcriptionally regulated by IL-1 in glioblastoma cells, and this pathway may be important in regulating survival and invasiveness of glioblastoma cells.
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PMID:Interleukin-1 regulates the expression of sphingosine kinase 1 in glioblastoma cells. 1907 42

Macrophages induce acute renal injury in anti-glomerular basement membrane (GBM) glomerulonephritis. This operates, in part, via activation of the c-Jun amino terminal kinase (JNK) signaling pathway. However, it is unknown whether inhibition of JNK signaling is effective once the proinflammatory response is established in the injured kidney. This study examined whether blockade of JNK signaling could halt disease progression, including crescent formation, in a model of severe crescentic anti-GBM glomerulonephritis. WKY rats were immunized with sheep IgG and then injected with sheep anti-GBM serum (day 0). Animals were treated with the JNK inhibitor, CC-401, vehicle alone, or no treatment from day 7 until being killed on day 24 of disease. Untreated animals at day 7 showed significant proteinuria, focal glomerular lesions, marked glomerular macrophage and T-cell accumulation, and upregulation of proinflammatory mediators (TNF-alpha, iNOS, MMP-12). Untreated and vehicle-treated groups displayed severe glomerulonephritis at day 24 with renal impairment and worsening proteinuria. These animals had severe glomerular lesions, with 60% of glomeruli exhibiting fibrocellular crescents, in association with increased macrophage and T-cell accumulation (including macrophage giant cells) and a further increase in mRNA levels of TNF-alpha, iNOS, MMP-12, and TGF-beta1. In contrast, CC-401 treatment prevented renal impairment, suppressed proteinuria, and prevented severe glomerular and tubulointerstitial lesions, including crescent formation and granulomatous-like lesions. These protective effects were independent of glomerular macrophage and T-cell accumulation, and of the humoral immune response. CC-401 treatment inhibited expression of both pro- and antiinflammatory molecules (interleukin-10 and heme oxygenase-1). In addition, IL-1 induced MMP-12 and IL-10 production by cultured macrophages was found to be JNK dependent. In conclusion, blockade of JNK signaling provides substantial protection against the progression of crescentic anti-GBM glomerulonephritis, which may be, in part, due to inhibition of the macrophage proinflammatory response.
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PMID:Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat. 1918 13

Here we investigate the potential of PCL-b-PEO micelles in preventing the cell death of isolated human islets of Langerhans. PCL-b-PEO micelles were loaded with c-Jun NH2-terminal kinases inhibitor SP600125 to rescue the isolated islets. Mechanistic studies of the uptake were conducted in PC12 cells. Incorporation of SP600125 afforded 8.2 fold greater solubility of SP600125 in micelle suspension. To investigate the effectiveness of micelle-incorporated SP600125 in preventing the islet cell death, we challenged the islets with TNF-alpha, IL-1, and IFN gamma. Micelle-incorporated SP600125 did not lose its inhibitory activity during incorporation into micelles, and it protected the islets against cytokine-induced loss of viability to the same extent as control SP600125. Moreover, the concentration of micelle-incorporated SP600125 used was 13-fold lower, demonstrating the greater efficacy of micelle delivered SP600125. Micelles maintained their cytoplasmic distribution without detectable nuclear localization in islets. The inhibition of JNK was confirmed by western blots. This study suggests that micelle-based intracellular delivery of potent, poorly water soluble, cell-death-pathway inhibitors may represent a valuable addition to established delivery of cytocidal block-copolymer micelle-incorporated bioactives.
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PMID:Block-copolymer micelles as carriers of cell signaling modulators for the inhibition of JNK in human islets of Langerhans. 1934 94

Obesity is an important risk factor for osteoarthritis (OA) in weight-bearing joints, but also in hand joints, pointing to an obesity-related metabolic factor that influences on the pathogenesis of OA. Leptin is an adipokine regulating energy balance, and it has recently been related also to arthritis and inflammation as a proinflammatory factor. In the present paper, the effects of leptin on human OA cartilage were studied. Leptin alone or in combination with IL-1 enhanced the expression of iNOS and COX-2, and production of NO, PGE(2), IL-6, and IL-8. The results suggest that the effects of leptin are mediated through activation of transcription factor nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathway c-Jun NH(2)-terminal kinase (JNK). Interestingly, inhibition of leptin-induced NO production with a selective iNOS inhibitor 1400 W inhibited also the production of IL-6, IL-8, and PGE(2), and this was reversed by exogenously added NO-donor SNAP, suggesting that the effects of leptin on IL-6, IL-8, and PGE(2) production are dependent on NO. These findings support the idea of leptin as a factor enhancing the production of proinflammatory factors in OA cartilage and as an agent contributing to the obesity-associated increased risk for osteoarthritis.
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PMID:Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage--mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production. 1968 9

(Pro)renin receptor (PRR) is present in renal glomeruli, and its expression is up-regulated in diabetes. Similarly, renal inflammation is increased in the presence of hyperglycemia. The linkage between PRR and renal inflammation is not well established. We hypothesized that glucose-induced up-regulation of PRR leads to increased production of the proinflammatory factors IL-1beta and cyclooxygenase-2 (COX-2). Studies were conducted in rat mesangial cells (RMCs) exposed to 30 mm D-glucose for 2 wk followed by PRR small interfering RNA knockdown, IL-1 receptor blockade with IL-1 receptor antagonist or angiotensin II type 1 receptor blockade with valsartan. The results showed that D-glucose treatment up-regulates prorenin, renin, angiotensin II, PRR, IL-1beta, and COX-2 mRNA and protein expression and increases phosphorylation of ERK1/2, c-Jun N-terminal kinase, c-Jun, and nuclear factor-kappaB (NF-kappaB) p65 (serine 276,468 and 536), respectively. PRR small interfering RNA attenuated PRR, IL-1beta, and COX-2 mRNA and protein expressions and significantly decreased angiotensin II production and phosphorylation of ERK1/2 and NF-kappaB p65 associated with high glucose exposure. Similarly, IL-1 receptor antagonist significantly reduced COX-2 mRNA and protein expression induced by high glucose. COX-2 inhibition reduced high-glucose-induced PRR expression. We conclude that glucose induces the up-regulation of PRR and its ligands prorenin and renin, leading to increased IL-1beta and COX-2 production via the angiotensin II-dependent pathway. It is also possible that PRR could enhance the production of these inflammatory cytokines through direct stimulation of ERK1/2-NF-kappaB signaling cascade.
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PMID:Glucose promotes the production of interleukine-1beta and cyclooxygenase-2 in mesangial cells via enhanced (Pro)renin receptor expression. 1986 3

Human bladder cancer has been associated with chronic exposure to arsenic. Chronic exposure of an immortalized non-tumorigenic urothelial cell line (UROtsa cells) to arsenicals has transformed these cells to a malignant phenotype, but the involved mechanisms are not fully understood. Chronic inflammation has been linked with cancer development mainly because many pro-inflammatory cytokines, growth factors as well as angiogenic chemokines have been found in tumors. In this study the chronology of inflammatory cytokines production was profiled in UROtsa cells chronically exposed to the toxic arsenic metabolite, monomethylarsonous acid [50 nM MMA(III)] to know the role of inflammation in cell transformation. Acute 50 nM MMA(III) exposure induced over-production of many pro-inflammatory cytokines as soon as 12 h after acute exposure. The same cytokines remain over-regulated after chronic exposure to 50 nM MMA(III), especially after 3 mo exposure. At 3 mo exposure the sustained production of cytokines like IL-1, IL-6, IL-8 and TNF is coincident with the appearance of characteristics associated with cell transformation seen in other arsenic-UROtsa studies. The sustained and increased activation of NFkappaB and c-Jun is also present along the transformation process and the phosphorylated proteins p38 MAPK and ERK 1/2 are increased also through the time line. Taken together these results support the notion that chronic inflammation is associated within MMA(III)-induced cell transformation and may act as a promoting factor in UROtsa cell transformation.
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PMID:Low level exposure to monomethyl arsonous acid-induced the over-production of inflammation-related cytokines and the activation of cell signals associated with tumor progression in a urothelial cell model. 2004 30


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