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

IL-13 is known to suppress the production of inflammatory cytokines such as TNF. Whether IL-13 also modulates the biologic effects of TNF is not known. In the present report we examined the effect of IL-13 on TNF-induced activation of nuclear transcription factors NF-kappa B and activation protein-1 (AP-1) and apoptosis. Pretreatment of cells with IL-13 blocked TNF-induced NF-kappa B activation, nuclear translocation of p65 subunit, and degradation of I kappa B alpha. IL-13 also inhibited NF-kappa B activation by LPS, okadaic acid, H2O2, and ceramide. TNF-induced NF-kappa B-dependent gene transcription was also blocked by IL-13. TNF-induced activation of another nuclear transcription factor, AP-1, was suppressed by IL-13. The activation of N-terminal c-Jun kinase and mitogen-activated protein kinase kinase, implicated in the regulation of AP-1 and NF-kappa B, was also down-regulated by IL-13. TNF-mediated cytotoxicity and activation of caspase-3 were abolished by IL-13. The inhibitory effects of IL-13 on TNF were sensitive to H-7, neomycin, and wortmannin, suggesting that the pathway consisting of protein kinase C, phosphatidylinositol 3-kinase, and phospholipase C must be involved in IL-13 signaling. Thus, overall, these results demonstrate that IL-13 is a potent inhibitor of TNF-mediated activation of NF-kappa B, AP-1, and apoptosis, which may contribute to its previously described immunosuppressive and anti-inflammatory effects.
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PMID:IL-13 suppresses TNF-induced activation of nuclear factor-kappa B, activation protein-1, and apoptosis. 974 47

Numerous investigations show that cytokines have a significant role in the regulation of cell growth. There is also increasing evidence for the role of transcription factors in cytokine-mediated growth-regulation of cancer cells. Our previous data demonstrate that several cytokines are able to inhibit DNA synthesis of vulvar carcinoma cells. The aim of this study was to investigate the effect of growth-inhibitory cytokines on the binding activity of transcription factor AP-1 and NF-kappaB in two vulvar carcinoma cell lines UM-SCV-6 and UM-SCV-1A in vitro. The effects of interferon gamma (IFN-gamma), interleukins 10 (IL-10) and 13 (IL-13), transforming growth factor beta(1) (TGF-beta(1)) and tumor necrosis factor alpha (TNF-alpha) on the DNA binding proteins were studied by electrophoretic mobility shift assay (EMSA). Our results showed that NF-kappaB and AP-1 were constitutively activated in both cell lines. The binding activity of NF-kappaB was found to be stimulated by TNF-alpha in both vulvar carcinoma cell lines while no effect on AP-1 was found by any of the cytokines. The binding activity of NF-kappaB was decreased by IL-10 and IL-13 in UM-SCV-1A cells suggesting that the pathway by which TNF-alpha activates NF-kappaB differs from that activated by interleukins.
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PMID:Activation of transcription factor NF-kappaB by growth inhibitory cytokines in vulvar carcinoma cells. 1099 84

Toll-like receptors (TLRs) are mammalian homologues of the Drosophila Toll receptors and are thought to have roles in innate recognition of bacteria. We demonstrated that TLR 2, 4, 6, and 8 but not TLR5 were expressed on mouse bone marrow-derived mast cells (BMMCs). Using BMMCs from the genetically TLR4-mutated strain C3H/HeJ, we demonstrated that functional TLR4 was required for a full responsiveness of BMMCs to produce inflammatory cytokines (IL-1beta, TNF-alpha, IL-6, and IL-13) by LPS stimulation. TLR4-mediated stimulation of mast cells by LPS was followed by activation of NF-kappaB but not by stress-activated protein kinase/c-Jun NH2-terminal kinase signaling. In addition, in the cecal ligation and puncture-induced acute septic peritonitis model, we demonstrated that genetically mast cell-deficient W/W(v) mice that were reconstituted with TLR4-mutated BMMCs had significantly higher mortality than W/W(v) mice reconstituted with TLR4-intact BMMCs. Higher mortality of TLR4-mutated BMMC-reconstituted W/W(v) mice was well correlated with defective neutrophil recruitment and production of proinflammatory cytokines in the peritoneal cavity. Taken together, these observations provide definitive evidence that mast cells play important roles in exerting the innate immunity by releasing inflammatory cytokines and recruitment of neutrophils after recognition of enterobacteria through TLR4 on mast cells.
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PMID:Protective roles of mast cells against enterobacterial infection are mediated by Toll-like receptor 4. 1149 12

Polyunsaturated fatty acids (PUFAs) are known to suppress inflammatory and autoimmune responses and, therefore, clinical applications of PUFAs as immunomodulatory substances are extensively studied. PUFAs are known to inhibit T cell responses, but with respect to TCR/CD3-mediated signal transduction only a block in CD3-induced phospholipase Cgamma1/calcium signaling has been shown so far. In this study, we investigated PUFA-mediated changes in downstream T cell signal transduction. We show that among the mitogen-activated protein kinase families activation of c-Jun NH(2)-terminal kinase, but not phosphorylation of extracellular signal-regulated kinase-1/-2 or p38 is inhibited. CD3/CD28-induced activity of NF-AT was markedly reduced by PUFA treatment, while activation of other nuclear receptors (AP-1 and NF-kappaB) remained unaltered. Furthermore, IL-2 promoter activity, IL-2 and IL-13 mRNA levels, IL-2 secretion, and IL-2R alpha-chain expression were significantly diminished by PUFA treatment, whereas the expression of IFN-gamma, IL-4, IL-10, and CD69 remained essentially unaffected by PUFAs. In conclusion, PUFA treatment of T cells inhibits selectively c-Jun NH(2)-terminal kinase and NF-AT activation, resulting in diminished production of IL-2 and IL-13.
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PMID:Suppression of T cell signaling by polyunsaturated fatty acids: selectivity in inhibition of mitogen-activated protein kinase and nuclear factor activation. 1279 31

The antigen stimulation of RBL-2H3 cells induced interleukin 13 (IL-13) production, which was inhibited by the steroidal anti-inflammatory drug dexamethasone and by the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Dexamethasone did not inhibit the antigen-induced phosphorylation of JNK but inhibited that of c-Jun. In a cell-free system, the phosphorylation of glutathione S-transferase-fused c-Jun by recombinant JNK was not inhibited by dexamethasone but was inhibited by the addition of recombinant glucocorticoid receptor (GR). These findings suggest that the inhibition of antigen-induced IL-13 production by dexamethasone is due to the GR-mediated inhibition of c-Jun phosphorylation induced by JNK.
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PMID:Inhibition by dexamethasone of interleukin 13 production via glucocorticoid receptor-mediated inhibition of c-Jun phosphorylation. 1462 17

Chemokine synthesis by airway smooth muscle cells (ASMC) may be an important process underlying inflammatory cell recruitment in airway inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Fractalkine (FKN) is a recently described CX(3)C chemokine that has dual functions, serving as both a cell adhesion molecule and a chemoattractant for monocytes and T cells, expressing its unique receptor, CX(3)CR1. We investigated FKN expression by human ASMC in response to the proinflammatory cytokines IL-1beta, TNF-alpha, and IFN-gamma, the T helper 2-type cytokines IL-4, IL-10, and IL-13, and the fibrogenic cytokine transforming growth factor (TGF)-beta. Neither of these cytokines alone had any significant effect on ASMC FKN production. Combined stimulation with IFN-gamma and TNF-alpha induced FKN mRNA and protein expression in a time- and concentration-dependent manner. TGF-beta had a significant inhibitory effect on cytokine-induced FKN mRNA and protein expression. Dexamethasone (10(-8)-10(-6) M) significantly upregulated cytokine-induced FKN mRNA and protein expression. Finally, we used selective inhibitors of the mitogen-activated protein kinases c-Jun NH(2)-terminal kinase (JNK) (SP-610025), p38 (SB-203580), and extracellular signal-regulated kinase (PD-98095) to investigate their role in FKN production. SP-610025 (25 microM) and SB-203580 (20 microM), but not PD-98095, significantly attenuated cytokine-induced FKN protein synthesis. IFN-gamma- and TNF-alpha-induced JNK phosphorylation remained unaltered in the presence of TGF-beta but was inhibited by dexamethasone, indicating that JNK is not involved in TGF-beta- or dexamethasone-mediated regulation of FKN production. In summary, FKN production by human ASMC in vitro is regulated by inflammatory and anti-inflammatory factors.
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PMID:Fractalkine/CX3CL1 production by human airway smooth muscle cells: induction by IFN-gamma and TNF-alpha and regulation by TGF-beta and corticosteroids. 1532 87

In synergy with stem cell factor (SCF), IL-4 strongly enhances mast cell proliferation and shifts IgE-dependent cytokine production in mature human mast cells toward an increased release of Th2 cytokines such as IL-3, IL-5, and IL-13 and a decreased IL-6 expression. In this study we analyzed the kinetics and the mechanisms of these IL-4 effects on mast cells purified from intestinal tissue. If the cells were first cultured with IL-4 for 14 days and then without IL-4 for another 14 days, mast cells lost the capacity of producing higher amounts of Th2 cytokines and regained the capacity of producing IL-6. The IL-4-induced up-regulation of mast cell proliferation and FcepsilonRI expression was also reversible if IL-4 was withdrawn for 14 days. Interestingly, in contrast to IL-4, proliferation and phenotype of human intestinal mast cells were not affected by IL-13 although both cytokines were capable of inducing STAT6 activation. Instead, IL-4 treatment (but not IL-13 treatment) was associated with an increased activity of ERK1/2 and c-Fos, the downstream target of ERK1/2 and component of the transcription factor AP-1. Consistently, mast cell proliferation and cytokine expression in response to IL-4 was blocked by the MEK inhibitor PD98059. In summary, our data show that the IL-4 effects on human intestinal mast cell functions are reversible and accompanied by an increased activity of ERK1/2 and c-Fos.
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PMID:IL-4-induced priming of human intestinal mast cells for enhanced survival and Th2 cytokine generation is reversible and associated with increased activity of ERK1/2 and c-Fos. 1590 15

The expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) on human gingival fibroblasts (HGF) may be important for migration and retention of inflammatory cells in periodontally diseased tissue. This study aimed to assess which cytokines regulate ICAM-1 and VCAM-1 expression on HGF. Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma enhanced both ICAM-1 and VCAM-1 expression on HGF. Interleukin (IL)-1beta mainly up-regulated ICAM-1 expression. On the other hand, IL-4 and IL-13 enhanced only VCAM-1 expression on HGF. IL-10 did not modulate both ICAM-1 and VCAM-1 expression. Transforming growth factor (TGF)-beta1 enhanced ICAM-1 expression. However, TGF-beta1 inhibited the VCAM-1 expression induced by TNF-alpha or IL-4. Both ICAM-1 and VCAM-1 expression by HGF was inhibited by nuclear factor-kappaB (NF-kappaB) activation inhibitor (MG-132). Mitogen-activated protein kinases (MAPK) inhibitors did not influence ICAM-1 expression induced by TNF-alpha. Interestingly, VCAM-1 expression was enhanced by MEK inhibitor (PD98059) and c-Jun NH2-terminal kinase (JNK) inhibitor (SP600125). These results mean that the balance of cytokines in periodontally diseased tissue may be essential for control of ICAM-1 and VCAM-1 expression on HGF, and the balance of ICAM-1 and VCAM-1 expression might be important for regulation of leucocytes infiltration and retention in periodontally diseased tissue.
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PMID:Cytokines differentially regulate ICAM-1 and VCAM-1 expression on human gingival fibroblasts. 1673 19

The Th2 cytokines interleukin (IL)-4 and IL-13 and chemokine monocyte chemoattractant protein-1 (MCP-1) are significantly involved in bronchial hyperreactivity (BHR) and remodelling in allergic asthma. Although IL-4 and IL-13 can regulate a number of chemokines from bronchial epithelium, their regulatory effect on the expression of MCP-1 is as yet unproved. We aim to investigate the intracellular signalling mechanisms of IL-4 and IL-13 regulating the expression and secretion of MCP-1 from human bronchial epithelial cells. BEAS-2B cells, derived from a human bronchial epithelial cell line, were activated with or without IL-4 and/or IL-13 for different time intervals. MCP-1 gene expression and protein secretion were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Activation of signalling molecules p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and Janus kinase-2 (JAK-2) was accessed by Western blotting. IL-4 and IL-13 were found to up-regulate gene expression and significantly increase the release of MCP-1 from BEAS-2B cells. Both cytokines could activate p38 MAPK, ERK and JAK-2, but not JNK activity. Inhibition of p38 MAPK, ERK and JAK-2 activities by pretreating the cells with their corresponding inhibitors SB203580, PD98059 and AG490, respectively, significantly suppressed IL-4- and IL-13-induced MCP-1 production in BEAS-2B cells. Together, the above results illustrate that the activation of p38 MAPK, ERK and JAK-2 but not JNK is crucial for IL-4- and IL-13-induced MCP-1 release in human bronchial epithelial cells. Our findings may provide insight into the future development of more effective therapeutic agents for treating allergic asthma.
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PMID:Interleukin (IL)-4 and IL-13 up-regulate monocyte chemoattractant protein-1 expression in human bronchial epithelial cells: involvement of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2 and Janus kinase-2 but not c-Jun NH2-terminal kinase 1/2 signalling pathways. 1679 87

Inflammation plays a key role in the pathogenesis of an AAA (abdominal aortic aneurysm); however, the nature of the inflammatory factors and cellular response(s) involved in AAA growth is controversial. In the present study, we set out to determine the aortic levels of inflammatory cytokines in relation to downstream inflammatory transcription factors and cellular responses. A comparison of AAA wall samples with atherosclerotic wall samples taken from the same aortic region allowed AAA-specific inflammatory parameters to be identified that distinguish AAAs from ASD (aortic atherosclerotic disease). RT-PCR (real-time PCR), ELISA, Western blotting and immunohistochemistry were combined to assess cytokines and transcription factors at the mRNA and protein level, and their activation status. Compared with ASD, inflammatory parameters associated with Th1-type [T-bet, IL (interleukin)-2, IFN-gamma (interferon-gamma), TNF-alpha (tumour necrosis factor-alpha), IL-1alpha and cytotoxic T-cells] and Th2-type [GATA3, IL-4, IL-10, IL-13 and B-cells] responses were all increased in AAA samples. Evaluation of major downstream inflammatory transcription factors revealed higher baseline levels of C/EBP (CCAAT/enhancer-binding protein) alpha, beta and delta in the AAA samples. Baseline p65 NF-kappaB (nuclear factor kappaB) and c-Jun [AP-1 (activator protein-1)] levels were comparable, but their activated forms were strongly increased in the AAA samples. Downstream target genes of p65 NF-kappaB, c-Jun, IL-6 and IL-8 were hyperexpressed. Molecular and cellular processes associated with IL-6 and IL-8 hyperactivation were enhanced in the AAA samples, i.e. the expression of phospho-STAT-3 (signal transducer and activator of transcription-3) and perforin were elevated, and the content of plasma cells, neutrophils and vasa vasorum was increased. In conclusion, our findings demonstrate that an AAA is a general inflammatory condition which is characterized by enhanced expression and activation of pro-inflammatory transcription factors, accompanied by IL-6 and IL-8 hyperexpression and exaggerated downstream cellular responses, which together clearly distinguish an AAA from ASD.
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PMID:Enhanced expression and activation of pro-inflammatory transcription factors distinguish aneurysmal from atherosclerotic aorta: IL-6- and IL-8-dominated inflammatory responses prevail in the human aneurysm. 1807 85


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