Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Under neuropathological conditions, reactive astrocytes release cytokines and chemokines, which act in an autocrine and/or paracrine fashion to modulate production of immunoregulatory factors from cells including microglia, astrocytes, and neurons. In this way, astrocytes play an important role in orchestrating immune responses within the central nervous system (CNS). Suppressor of cytokine signaling (SOCS) proteins are endogenous, negative regulators of the JAK/STAT signaling pathway and function as attenuators of the immune and inflammatory responses. As such, SOCS proteins may have critical roles in the CNS under neuroinflammatory conditions. In the inflamed CNS, expression of IL-6 cytokine family member oncostatin M (OSM) is elevated; however, its functional effects are not well understood. We demonstrate that OSM is a potent inducer of SOCS-3 in astrocytes. Analysis of the SOCS-3 promoter revealed that an AP-1 element, two IFN-gamma activation sequence (GAS) elements, and a GC-rich region are crucial for SOCS-3 gene expression. Using small interfering RNA against STAT-3, as well as a STAT-3 dominant-negative construct, we demonstrate that STAT-3 activation is critical for OSM induction of SOCS-3 expression. The ERK1/2 and JNK pathways also contribute to OSM-induced SOCS-3 gene expression. OSM stimulation led to a time-dependent recruitment of the transcription factors STAT-3, c-Fos, c-Jun, and Sp1 and the coactivators CREB-binding protein (CBP) and p300 to the endogenous SOCS-3 promoter. These data indicate that OSM-induced activation of STAT-3 and the ERK1/2 and JNK pathways are critical for astrocytic expression of SOCS-3, which provides for feedback inhibition of cytokine-induced inflammatory responses in the CNS.
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PMID:Molecular basis of oncostatin M-induced SOCS-3 expression in astrocytes. 1857 93

IFN-gamma production by T cells is pivotal for defense against many pathogens, and the proximal promoter of IFN-gamma, -73 to -48 bp upstream of the transcription start site, is essential for its expression. However, transcriptional regulation mechanisms through this promoter in primary human cells remain unclear. We studied the effects of cAMP response element binding protein/activating transcription factor (CREB/ATF) and AP-1 transcription factors on the proximal promoter of IFN-gamma in human T cells stimulated with Mycobacterium tuberculosis. Using EMSA, supershift assays, and promoter pulldown assays, we demonstrated that CREB, ATF-2, and c-Jun, but not cyclic AMP response element modulator, ATF-1, or c-Fos, bind to the proximal promoter of IFN-gamma upon stimulation, and coimmunoprecipitation indicated the possibility of interaction among these transcription factors. Chromatin immunoprecipitation confirmed the recruitment of these transcription factors to the IFN-gamma proximal promoter in live Ag-activated T cells. Inhibition of ATF-2 activity in T cells with a dominant-negative ATF-2 peptide or with small interfering RNA markedly reduced the expression of IFN-gamma and decreased the expression of CREB and c-Jun. These findings suggest that CREB, ATF-2, and c-Jun are recruited to the IFN-gamma proximal promoter and that they up-regulate IFN-gamma transcription in response to microbial Ag. Additionally, ATF-2 controls expression of CREB and c-Jun during T cell activation.
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PMID:CREB, ATF, and AP-1 transcription factors regulate IFN-gamma secretion by human T cells in response to mycobacterial antigen. 1864 43

Recently, we reported that silibinin inhibits primary lung tumor growth and progression in mice and down-regulates inducible nitric oxide synthase (iNOS) expression in tumors; however, the mechanisms of silibinin action are largely not understood. Also, the activation of signaling pathways inducing various transcription factors are associated with lung carcinogenesis and their inhibition could be an effective strategy to prevent and/or treat lung cancer. Herein, we used human lung epithelial carcinoma A549 cells to explore the potential mechanisms and observed strong iNOS expression by cytokine mixture (containing 100 units/mL IFN-gamma + 0.5 ng/mL interleukin-1beta + 10 ng/mL tumor necrosis factor-alpha). We also examined the cytokine mixture-activated signaling cascades, which could potentially up-regulate iNOS expression, and then examined the effect of silibinin (50-200 mumol/L) on these signaling cascades. Silibinin treatment inhibited, albeit to different extent, the cytokine mixture-induced activation of signal transducer and activator of transcription 1 (Tyr(701)), signal transducer and activator of transcription 3 (Tyr(705)), activator protein-1 family of transcription factors, and nuclear factor-kappaB. The results for activator protein-1 were correlated with the decreased nuclear levels of phosphorylated c-Jun, c-Jun, JunB, JunD, phosphorylated c-Fos, and c-Fos. Further, silibinin also strongly decreased cytokine mixture-induced phosphorylation of extracellular signal-regulated kinase 1/2 but only marginally affected JNK1/2 phosphorylation. Silibinin treatment also decreased constitutive p38 phosphorylation in the presence or absence of cytokine mixture. Downstream of these pathways, silibinin strongly decreased cytokine mixture-induced expression of hypoxia-inducible factor-1alpha without any considerable effect on Akt activation. Cytokine mixture-induced iNOS expression was completely inhibited by silibinin. Overall, these results suggest that silibinin could target multiple cytokine-induced signaling pathways to down-regulate iNOS expression in lung cancer cells and that could contribute to its overall cancer preventive efficacy against lung tumorigenesis.
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PMID:Silibinin inhibits cytokine-induced signaling cascades and down-regulates inducible nitric oxide synthase in human lung carcinoma A549 cells. 1864 94

Innate immune cells produce NO via inducible NO synthase (iNOS) in response to certain infections or upon stimulation with cytokines such as IFN-gamma and TNF. NO plays an important role in host defense against intracellular bacteria including Chlamydophila pneumoniae as a result of its microbicidal activity. In MyD88-deficient mice, which succumb to C. pneumoniae infection, iNOS induction is impaired 6 days postinfection, although pulmonary levels of IFN-gamma and TNF are elevated as in wild-type mice at this time-point. Here, we demonstrate that induction of iNOS in macrophages upon C. pneumoniae infection is controlled by MyD88 via two pathways: NF-kappaB activation and phosphorylation of the MAPK JNK, which leads to the nuclear translocation of c-Jun, one of the two components of the AP-1 complex. In addition, phosphorylation of STAT1 and expression of IFN regulatory factor 1 (IRF-1) were delayed in the absence of MyD88 after C. pneumoniae infection but not after IFN-gamma stimulation. Taken together, our data show that for optimal induction of iNOS during C. pneumoniae infection, the concerted action of the MyD88-dependent transcription factors NF-kappaB and AP-1 and of the MyD88-independent transcription factors phosphorylated STAT1 and IRF-1 is required.
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PMID:Induction of iNOS by Chlamydophila pneumoniae requires MyD88-dependent activation of JNK. 1879 52

Cisplatin, a chemotherapeutic drug, may also act as a biological response modifier. Cisplatin (10mug/ml) treatment of macrophages for 24h activates them to produce enhanced amounts of nitric oxide (NO), ROI, proinflammatory cytokines and exhibit increased tumoricidal activity, which may or may not be contact mediated. In the present investigation, we report that the treatment of macrophages with cisplatin for a short period of 2h is sufficient to make them more receptive to interaction with tumor cells. Macrophages pretreated with cisplatin for 2h, and co-incubated with L929 cells, produced enhanced NO, TNF-alpha, IL-1beta, IL-12 and IFN-gamma. Production of NO, TNF-alpha, IL-1beta, IL-12 and IFN-gamma was maximum at 24h of co-incubation. Enhanced transcription of iNOS, TNF-alpha, IL-1beta, IL-12 and IFN-gamma genes in cisplatin-pretreated macrophages were observed between 12 and 24h of co-incubation with L929 cells. Cisplatin-treated macrophages on co-incubation with L929 cells also expressed enhanced transcription of Toll-like receptor (TLR)-2 and TLR-4 genes and their proteins. It is observed that cisplatin-pretreated macrophages on co-incubation with L929 cells showed activation of mitogen-activated protein (MAP) kinases and NF-kappaB. Pharmacological inhibitors like PD98059, SB202190 and wortmannin strongly inhibited the production of NO and proinflammatory cytokines suggesting the probable role of p42/44, p38 MAPK and PI3K in the above process. The c-Jun amino terminal kinase (JNK) inhibitor SP600125 was less effective in inhibiting the production of NO and proinflammatory cytokines. The data thus suggests that pretreatment of macrophages with cisplatin makes them biologically more responsive to interaction with L929 cells and become activated.
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PMID:Cisplatin primes murine peritoneal macrophages for enhanced expression of nitric oxide, proinflammatory cytokines, TLRs, transcription factors and activation of MAP kinases upon co-incubation with L929 cells. 1921 2

The Mycobacterium tuberculosis early secreted Ag of 6 kDa (ESAT-6) is a potent Ag for human T cells and is a putative vaccine candidate. However, ESAT-6 also contributes to virulence in animal models, mediates cellular cytolysis, and inhibits IL-12 production by mononuclear phagocytes. We evaluated the effects of ESAT-6 and its molecular chaperone, culture filtrate protein of 10 kDa (CFP10), on the capacity of human T cells to produce IFN-gamma and proliferate in response to TCR activation. Recombinant ESAT-6, but not CFP10, markedly inhibited IFN-gamma production by T cells stimulated with M. tuberculosis or with the combination of anti-CD3 and anti-CD28, in a dose-dependent manner. ESAT-6 also inhibited T cell production of IL-17 and TNF-alpha but not IL-2. Preincubation of ESAT-6 with CFP10 under conditions that favor dimer formation did not affect inhibition of IFN-gamma. ESAT-6 decreased IFN-gamma transcription and reduced expression of the transcription factors, ATF-2 and c-Jun, which normally bind to the IFN-gamma proximal promoter and stimulate mRNA expression. ESAT-6 inhibited T cell IFN-gamma secretion through mechanisms that did not involve cellular cytotoxicity or apoptosis. ESAT-6, but not CFP10, bound to T cells and inhibited expression of early activation markers without reducing activation of ZAP70. We conclude that ESAT-6 directly inhibits human T cell responses to mycobacterial Ags by affecting TCR signaling pathways downstream of ZAP70.
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PMID:ESAT-6 inhibits production of IFN-gamma by Mycobacterium tuberculosis-responsive human T cells. 1926 45

The aim of the present study was to evaluate the role of endogenous and exogenous peroxisome proliferator-activated receptor alpha (PPAR-alpha), a nuclear receptor, on the regulation of inflammation in macrophages. To address this question, we have stimulated peritoneal macrophages from PPAR-alpha wild-type mice and PPAR-alpha knockout mice (PPAR-alpha) with 10 microg/mL LPS and 100 U/mL IFN-gamma. We report here that the absence of a functional PPAR-alpha gene in PPAR-alpha knockout mice resulted in a significant augmentation of various inflammatory parameters in peritoneal macrophages. In particular, we have clearly demonstrated that PPAR-alpha gene deletion increases (1) the mitogen-activated protein kinase phosphorylation (extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38), (2) nuclear factor-kappaB activation, (3) IkappaB-alpha degradation, (4) iNOS expression and NO formation, and (5) cyclooxygenase 2 expression and prostaglandin E2 formation caused by LPS/IFN-gamma stimulation. On the contrary, the incubation of peritoneal macrophages from PPAR-alpha wild type with clofibrate (2 mM) at 2 h before the LPS and IFN-gamma stimulation significantly reduced the expression and the release of the proinflammatory mediators. To elucidate whether the protective effects of clofibrate is related to activation of the PPAR-alpha receptor, we also investigated the effect of clofibrate treatment on PPAR-alpha-deficient mice. The absence of the PPAR-alpha receptor significantly abolished the protective effect of the PPAR-alpha agonist against LPS/IFN-gamma-induced macrophage inflammation. In conclusion, our study demonstrates that the endogenous and exogenous PPAR-alpha ligands reduce the degree of macrophage inflammation caused by LPS/IFN-gamma stimulation.
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PMID:The role of endogenous and exogenous ligands for the peroxisome proliferator-activated receptor alpha (PPAR-alpha) in the regulation of inflammation in macrophages. 1953 51

Oxidative/nitrosative stress and generation of proinflammatory cytokines are hallmarks of inflammation. Because chronic inflammation is implicated in several pathologic conditions in humans, including cancers of the colon, anti-inflammatory compounds may be useful chemopreventive agents against colon cancer. Stilbenes, such as resveratrol, have diverse pharmacologic activities, which include anti-inflammation, cancer prevention, a cholesterol-lowering effect, enhanced insulin sensitivity, and increased life span. We previously showed that pterostilbene (trans-3,5-dimethoxy-4'-hydroxystilbene), a structural analogue of resveratrol, is present in blueberries and that pterostilbene inhibited expression of certain inflammation-related genes in the colon and suppressed aberrant crypt foci formation in rats. Here, we examined molecular mechanisms of the action of pterostilbene in colon cancer. Pterostilbene reduced cell proliferation, down-regulated the expression of c-Myc and cyclin D1, and increased the level of cleaved poly(ADP-ribose) polymerase. A combination of cytokines (tumor necrosis factor-alpha, IFN-gamma, and bacterial endotoxin lipopolysaccharide) induced inflammation-related genes such as inducible nitric oxide synthase and cyclooxygenase-2, which was significantly suppressed by treatment with pterostilbene. We further identified upstream signaling pathways contributing to the anti-inflammatory activity of pterostilbene by investigating multiple signaling pathways, including nuclear factor-kappaB, Janus-activated kinase-signal transducer and activator of transcription, extracellular signal-regulated kinase, p38, c-Jun NH(2)-terminal kinase, and phosphatidylinositol 3-kinase. Cytokine induction of the p38-activating transcription factor 2 pathway was markedly inhibited by pterostilbene among the different mediators of signaling evaluated. By silencing the expression of the p38 alpha isoform, there was significant reduction in cytokine induction of inducible nitric oxide synthase and cyclooxygenase-2. Our data suggest that the p38 mitogen-activated protein kinase cascade is a key signal transduction pathway for eliciting the anti-inflammatory action of pterostilbene in cultured HT-29 colon cancer cells.
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PMID:Anti-inflammatory action of pterostilbene is mediated through the p38 mitogen-activated protein kinase pathway in colon cancer cells. 1954 98

Cytotoxic T lymphocytes (CTL) may undergo massive expansion upon appropriate antigenic stimulation. Homeostasis is maintained by a subsequent "contraction" of these cells. Activation-induced cell death (AICD) and programmed cell death prevent the untoward side effects, arising from excessive numbers and prolonged persistence of activated CTL, that occur upon uncontrolled and/or continued expansion. However, effector cell persistence has been identified as a hallmark of successful T-cell-mediated adoptive immunotherapy. Thus, prevention of AICD may be critical to achieve more successful clinical results. We have previously shown that treatment with the c-Jun NH(2)-terminal kinase (JNK) inhibitor SP600125 protects human melanoma epitope Mart-1(27-35)-reactive CTL from apoptotic death upon their reencounter with cognate antigen. However, inhibition of JNK also interferes with the functional ability of the CTL to secrete IFN-gamma. Here, we show that reactive oxygen species (ROS) inhibitors, such as the superoxide dismutase mimetic Mn (III) tetrakis (5, 10, 15, 20-benzoic acid) porphyrin (MnTBAP), efficiently protected Mart-1(27-35)-reactive primary CTL from AICD without impairing their functional capability. MnTBAP prevented the increase in intracellular ROS, mitochondrial membrane collapse, and DNA fragmentation observed in control-treated cells upon cognate antigen encounter. Furthermore, the mechanism of AICD prevention in primary CTL included blockade of JNK activation. Finally, tumor-reactive in vitro expanded tumor infiltrating lymphocytes, which are used clinically in cancer immunotherapy, also benefit from MnTBAP-mediated antioxidant treatment. Thus, modulation of the redox pathway might improve CTL persistence and lead to better clinical results for T cell-based immunotherapies.
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PMID:Inhibition of superoxide generation upon T-cell receptor engagement rescues Mart-1(27-35)-reactive T cells from activation-induced cell death. 1963 95

Studies of patients with active tuberculosis (TB) and infected healthy individuals have shown that interferon (IFN)-gamma is present in sites of Mycobacterium tuberculosis infection in comparable levels. This suggests that there is a deficiency in the macrophage response to IFN-gamma in TB patients. We used recombinant human IFN-gamma to stimulate adherent monocyte-derived macrophages from three groups of people: patients with active tuberculosis (TBP), their healthy household contacts (HHC) and healthy uninfected controls from the community (CC). We then evaluated the ability of the macrophages to inhibit the growth of M. tuberculosis H37Rv as well as their cytokine profile at early in infection (48 h). After IFN-gamma treatment, macrophages of healthy individuals (HHC and CC) controlled M. tuberculosis growth and produced mainly nitric oxide (NO) and interleukin (IL)-12p70, whereas TBP macrophages did not kill M. tuberculosis. Additionally, TBP macrophages produced low levels of NO and IL-12p70 and high levels of tumour necrosis factor (TNF)-alpha and IL-10. Transforming growth factor (TGF)-beta levels were similar among all three groups. M. tuberculosis infection had little effect on the cytokine response after IFN-gamma stimulus, but infection alone induced more IL-10 and TGF-beta in TBP macrophages. There were no differences in Stat1 nuclear translocation and DNA binding between the groups. However, the phosphorylated Stat1 and c-Jun (AP-1) in nuclear protein extracts was diminished in TBP macrophages compared to macrophages of healthy individuals. These results indicate an impairment of Stat1-dependent and Stat1-independent IFN-gamma signalling in macrophages of people with active tuberculosis, suggesting a different molecular regulation that could impact macrophage functionality and disease outcome.
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PMID:Impaired activation of Stat1 and c-Jun as a possible defect in macrophages of patients with active tuberculosis. 1973 30


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