Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signaling through its widely distributed cell surface receptor, interleukin (IL)-17 enhances the transcription of genes encoding proinflammatory molecules. Although it has been well documented that IL-17 activates the transcription factor nuclear factor (NF)-kappaB and c-Jun NH(2)-terminal kinase (JNK), the upstream signaling events are largely unknown. Here we report the requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in IL-17-induced NF-kappaB and JNK activation. In embryonic fibroblasts (EFs) derived from TRAF6 knockout mice, IL-17 failed to activate the IkappaB kinases (IKKs) and JNK. Consequently, IL-17-induced IL-6 and intercellular adhesion molecule 1 expression in the TRAF6-deficient cells was abolished. Lack of TRAF6 appeared to be the sole defect responsible for the observed failure to respond to IL-17, because transient transfection of TRAF6 expression plasmid into the TRAF6-deficient cells restored IL-17-induced NF-kappaB activation in a luciferase reporter assay. Furthermore, the levels of IL-17 receptor (IL-17R) on the TRAF6-deficient EFs were comparable to those on the wild-type control cells. Defect in IL-17 response was not observed in TRAF2-deficient EFs. Moreover, when TRAF6 and IL-17R were coexpressed in 293 cells, TRAF6 coimmunoprecipitated with IL-17R. Together, these results indicate that TRAF6, but not TRAF2, is a crucial component in the IL-17 signaling pathway leading to proinflammatory responses.
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PMID:Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. 1074 40

In cardiac myocytes, the stimulation of p38 MAPK by the MAPKK, MKK6, activates the transcription factor, NF-kappaB, and protects cells from apoptosis. In the present study in primary neonatal rat cardiac myocytes, constitutively active MKK6, MKK6(Glu), bound to IkappaB kinase (IKK)-beta and stimulated its abilities to phosphorylate IkappaB and to activate NF-kappaB. MKK6(Glu) induced NF-kappaB-dependent interleukin (IL)-6 transcription and IL-6 release in a p38-dependent manner. IL-6 protected myocardial cells against apoptosis. Like IL-6, TNF-alpha, which activates both NF-kappaB and p38, also induced p38-dependent IL-6 expression and release and protected myocytes from apoptotis. While TNF-alpha was relatively ineffective, IL-6 activated myocardial cell STAT3 by about 8-fold, indicating a probable role for this transcription factor in IL-6-mediated protection from apoptosis. TNF-alpha-mediated IL-6 induction was inhibited by a kinase-inactive form of the MAPKKK, TGF-beta activated protein kinase (Tak1), which is known to activate p38 and NF-kappaB in other cell types. Thus, by stimulating both p38 and NF-kappaB, Tak1-activating cytokines, like TNF-alpha, can induce IL-6 expression and release. Moreover, the myocyte-derived IL-6 may then function in an autocrine and/or paracrine fashion to augment myocardial cell survival during stresses that activate p38.
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PMID:p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system. 1078 14

As a result of identifying the regulatory proteins of thioredoxin (TRX), a murine homologue for human vitamin D3 up-regulated protein 1 (VDUP1) was identified from a yeast two-hybrid screen. Cotransfection into 293 cells and precipitation assays confirmed that mouse VDUP1 (mVDUP1) bound to TRX, but it failed to bind to a Cys32 and Cys35 mutant TRX, suggesting the redox-active site is critical for binding. mVDUP1 was ubiquitously expressed in various tissues and located in the cytoplasm. Biochemical analysis showed that mVDUP1 inhibited the insulin-reducing activity of TRX. When cells were treated with various stress stimuli such as H2O2 and heat shock, mVDUP1 was significantly induced. TRX is known to interact with other proteins such as proliferation-associated gene and apoptosis signal-regulating kinase 1. Coexpression of mVDUP1 interfered with the interaction between TRX and proliferation-associated gene or TRX and ASK-1, suggesting its roles in cell proliferation and oxidative stress. To investigate the roles of mVDUP1 in oxidative stress, mVDUP1 was overexpressed in NIH 3T3 cells. When cells were exposed to stress, cell proliferation was declined with elevated apoptotic cell death compared with control cells. In addition, c-Jun N-terminal kinase activation and IL-6 expression were elevated. Taken together, these results demonstrate that mVDUP1 functions as an oxidative stress mediator by inhibiting TRX activity.
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PMID:Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. 1084 82

Computer analysis of the human placental lactogen-B (hPL-B) enhancer reveals two putative binding sites for the transcription factor NF-IL6, but the role of NF-IL6 in the regulation of the enhancer is unknown. Using gel mobility shift and supershift assays, we demonstrated that NF-IL6 binds to both enhancer sites. Transient transfection studies indicated that the transcription factor NF-IL6 stimulates hPL-B enhancer activity by 4.4-fold in primary cultures of human trophoblast cells and by 32.0- and 8.4-fold in JAR and BeWo choriocarcinoma cells, respectively. Overexpression of MEK (mitogen-activated protein [MAP] kinase kinase), which is known to stimulate phosphorylation of NF-IL6, induced a 3.6-fold increase in hPL-B enhancer activity. The induction by MEK was completely inhibited by an expression plasmid for a dominant/negative mutant of NF-IL6 or by mutation of the NF-IL6 binding sites on the enhancer. PD98059, an inhibitor of MEK, inhibited hPL release from cultured trophoblast cells by about 50%. Taken together, these results indicate that MAP kinase stimulates the hPL-B enhancer by an NF-IL-6-dependent pathway.
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PMID:Mitogen-activated protein kinase activates human placental lactogen-B enhancer by an NF-IL6-dependent pathway. 1085 90

This study aimed to investigate the time-course of the effect of beta2-adrenoceptor stimulation with terbutaline on lipopolysaccharide (LPS)-induced tumour necrosis factor(TNF)-alpha production in rat mesangial cells. Cells were cultured from 0-24 h in the presence of LPS (1 microg/ml) and/or terbutaline (10(-7)-10(-8) mol/l). After 1 h of incubation, terbutaline inhibited TNF-alpha protein release as well as transcription and translation of TNF-alpha and mitogen activated protein kinase (MAPK, p42/p44) activity. At 3 h, terbutaline enhanced intracellular cAMP but suppressed TNF-alpha release and transcription. By 24 h, whereas terbutaline was no longer influencing transcription or translation, TNF-alpha release remained depressed which correlated with an increase in supernatant interleukin (IL)-6. Terbutaline did not affect the LPS-induced IL-10 produced in the cell. These findings indicate that beta2-adrenoceptor stimulation during an LPS challenge prevented TNF-alpha production as a consequence of MAPK inhibition and enhanced cAMP generation, which at a later stage was associated with an anti-inflammatory effect of IL-6.
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PMID:Beta2-adrenoceptor agonist suppresses tumour necrosis factor production in rat mesangial cells. 1085 65

Loss of ovarian function following menopause results in a substantial increase in bone turnover and a critical imbalance between bone formation and resorption. This imbalance leads to a progressive loss of trabecular bone mass and eventually osteoporosis, in part the result of increased osteoclastogenesis. Enhanced formation of functional osteoclasts appears to be the result of increased elaboration by support cells of osteoclastogenic cytokines such as IL-1, tumor necrosis factor, and IL-6, all of which are negatively regulated by estrogens. We show here that estrogen can suppress receptor activator of NF-kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF)-induced differentiation of myelomonocytic precursors into multinucleated tartrate-resistant acid phosphatase-positive osteoclasts through an estrogen receptor-dependent mechanism that does not require mediation by stromal cells. This suppression is dose-dependent, isomer-specific, and reversed by ICI 182780. Furthermore, the bone-sparing analogues tamoxifen and raloxifene mimic estrogen's effects. Estrogen blocks RANKL/M-CSF-induced activator protein-1-dependent transcription, likely through direct regulation of c-Jun activity. This effect is the result of a classical nuclear activity by estrogen receptor to regulate both c-Jun expression and its phosphorylation by c-Jun N-terminal kinase. Our results suggest that estrogen modulates osteoclast formation both by down-regulating the expression of osteoclastogenic cytokines from supportive cells and by directly suppressing RANKL-induced osteoclast differentiation.
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PMID:Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. 1086 27

The signal transduction pathways regulating smooth-muscle gene expression and production of cytokines in response to proinflammatory mediators are undefined. Cultured human bronchial smooth-muscle cells were treated for 20 h with a cytokine cocktail containing interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma. A complementary DNA expression array containing 588 genes was used to follow cytokine-stimulated gene expression. The expression and secretion of the cytokines IL-1beta, IL-6, and IL-8 significantly increased after 20 h of stimulation as measured by relative reverse transcriptase/ polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting techniques. Expression of IL-6 and IL-8 was sensitive to SB203580, the specific inhibitor of p38 mitogen-activated protein (MAP) kinase and PD98059, an inhibitor of MAP kinase kinase. Expression of IL-1beta was sensitive only to PD98059. Together, these results demonstrate that the p38 and extracellular signal-regulated protein kinase MAP kinase pathways are required for proinflammatory mediator- induced cytokine expression in airway myocytes. The generation of chemokines and cytokines in airway smooth muscle also provides evidence that smooth-muscle cells have the ability to contribute to the inflammatory response.
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PMID:Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes. 1087 57

Interleukin (IL)-6-related cytokines share gp130 as the signal-transducing protein. Cardiac myocytes produce various kinds of cytokines including IL-6 and cardiotrophin-1. Activation of gp130 transduces hypertrophic and cytoprotective signals in cardiac myocyte via JAK/STAT, MAP kinase and PI-3 kinase pathways. Besides various well-established mechanisms by which myocardial hypertrophy and remodeling are regulated, a gp130 signaling may be a newly discovered mechanism that regulates these events in association with cytoprotective effect in cardiomyopathy. In addition, the activation of gp130 dependent signaling pathway in cardiac myocytes might play a pivotal role in the prevention of heart failure.
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PMID:[Role of cytokine signaling in cardiomyopathy]. 1088 19

Oncostatin M (OSM) is a member of the interleukin (IL)-6 family of cytokines and has both pro- and anti-inflammatory properties. Of interest, OSM has functional effects within the CNS. We have shown recently that OSM can modulate expression of the cytokine IL-6 in astrocytes. Herein we characterize the molecular mechanisms and signaling cascades involved in this response. OSM induces IL-6 protein expression in a dose- and time-dependent manner in astrocytes. In addition, OSM can synergize with the cytokines tumor necrosis factor-alpha, IL-1beta, and transforming growth factor-beta for enhanced IL-6 expression. Using neutralizing antibodies to gp 130, the OSM receptor (OSMR), and the leukemia inhibitory factor receptor (LIFR), we document that OSM exclusively uses the OSMR/gp 130 heterodimer in signaling events, rather than the LIFR/gp 130 heterodimer. Kinetic analysis of OSM-induced IL-6 mRNA reveals two up-regulatory events. The first, peaking at 1 h, is transient, does not require protein synthesis, and is regulated at the transcriptional level. The second, peaking between 6 and 8 h, is prolonged and sensitive to puromycin, suggesting a requirement for de novo protein synthesis, and also is transcriptionally regulated. OSM-induced IL-6 mRNA and protein expression is inhibited by the mitogen-activated protein kinase (MAPK) inhibitors U0126 and SB202190, suggesting a requirement for the MAPKs ERK1/2 and p38 in this response. Finally, we show that the MAPKs ERK1/2 and p38 are activated by OSM in astrocytes and that this activation is reduced by the MAPK inhibitors. These data demonstrate that OSM induces IL-6 expression in astrocytes and that the MAPKs ERK1/2 and p38 participate in this response.
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PMID:Oncostatin M regulation of interleukin-6 expression in astrocytes: biphasic regulation involving the mitogen-activated protein kinases ERK1/2 and p38. 1089 31

Oncostatin M (OSM), a member of the hemopoietic cytokine family, has been implicated in the process of fibrosis and dermal wound healing. As a part of an ongoing study of the mechanisms of fibrosis and dermal wound healing, we have investigated the mechanism of the growth regulation of dermal fibroblasts by OSM. OSM stimulates the mitogenesis of dermal fibroblasts in a dose-dependent manner. This effect was completely blocked by anti-OSM IgG, but not by anti-IL-6 IgG. Furthermore, OSM induction was abolished by genistein, a tyrosine kinase inhibitor, or by PD98059, a specific mitogen-activated protein (MAP) kinase pathway inhibitor, but not by calphostin C, a protein kinase C inhibitor. Immunoblotting analysis using a specific Ab against phosphorylated MAP kinase (Thr202/Tyr204) showed that OSM induces phosphorylation of MAP kinase in dermal fibroblasts. Furthermore, transient transfection of the dominant-negative mutant MAP kinase into dermal fibroblasts abolished the OSM induction. These results strongly suggest that OSM stimulates the growth of dermal fibroblasts via a MAP kinase-dependent pathway.
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PMID:Oncostatin M stimulates the growth of dermal fibroblasts via a mitogen-activated protein kinase-dependent pathway. 1092 1


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