Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncostatin M (OM) is a member of the interleukin-6 (IL-6) cytokine subfamily. The binding of OM to its receptor initiates signal transduction through JAK-signal transducers and activators of transcription (STAT) pathways and activates transcription activators through mitogen-activated protein (MAP) kinases. Results of in vitro assays documented that OM modulates cytokine expression and alters the production of proteases that down-regulate inflammation. Administration of OM to lipopolysaccharide (LPS)-challenged mice lowered serum tumor necrosis factor-alpha (TNF-alpha) levels and decreased the lethal effects of LPS administration. OM also reduced inflammation in animal models of human disease, including inflammatory bowel disease, antibody-induced arthritis, and experimental autoimmune encephalomyelitis. Preclinical safety studies have been conducted in the mouse and monkey. Mice were administered OM (subcutaneously) at 72, 360, or 1,560 micrograms/kg/day in a 2-wk toxicity study. Decreased body weights occurred at 1,560 micrograms/kg. Drug-related changes at 360 and 1,560 micrograms/kg consisted of dermal irritation at the injection site, leukopenia, and thymic lymphoid depletion; all changes were reversible following a 2-wk recovery period. In a 2-wk subcutaneous study in monkeys, OM was administered at 1, 5, 15, 45, or 150 micrograms/kg/day. At all doses there was reversible, transient inappetence and dermal irritation at the injection site. Drug-related changes at 5, 15, 45, and 150 micrograms/kg consisted of reversible elevations in both serum amyloid A and IL-6, and reversible thymic lymphoid depletion. Transient increases in body temperature occurred at 15, 45, and 150 micrograms/kg. The observed spectrum of immunomodulatory effects suggests that OM may have therapeutic utility in treating chronic inflammatory diseases.
 ...
PMID:Oncostatin M: development of a pleiotropic cytokine. 1020 78

The single layer of epithelial cells lining the intestine that serves as an important physical and functional barrier regulating the uptake of nutrients and the exclusion of various environmental antigens is disrupted in inflammatory bowel diseases. A central cytokine in the pathogenesis of inflammatory bowel disease is tumor necrosis factor (TNF), which increases apoptosis in a number of cell types. However, details determining the fate of intestinal cells exposed to high levels of TNF are lacking. Our laboratory reported that kinase suppressor of Ras (KSR) regulates TNF activation of the Raf/mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase/ERK signaling cassette by threonine phosphorylation of Raf-1, regulating proliferation and differentiation pathways. In the present study, we expressed a dominant-negative kinase-inactive KSR and determined the survival of young adult mouse colon cells exposed to TNF. Our data show that inhibition of KSR signaling decreases survival and increases apoptosis of TNF-treated cells. Antiapoptotic pathways including nuclear factor kappa B activation and one of its transcriptional targets, cIAP2 (c inhibitor of apoptosis protein 2) gene expression, and ERK/MAP kinase activation are all inhibited in TNF-treated kinase-inactive KSR-expressing young adult mouse colon cells. These antiapoptotic pathways are also inhibited by antisense-mediated down-regulation of KSR. However, TNF activation of p38 or stress-activated protein kinase/c-Jun NH(2)-terminal kinase is not inhibited by disruption of KSR signaling. Furthermore, inhibitors of both ERK and nuclear factor kappa B activation synergistically enhance apoptosis of cells treated with TNF. These findings demonstrate that KSR plays a novel regulatory role in intestinal epithelial cells exposed to TNF by activating cell survival pathways.
 ...
PMID:Kinase suppressor of Ras determines survival of intestinal epithelial cells exposed to tumor necrosis factor. 1175 83

Inflammatory bowel disease of the colon is associated with a high osmolarity of colonic contents. We hypothesized that this hyperosmolarity may contribute to colonic inflammation by stimulating the proinflammatory activity of intestinal epithelial cells (IECs). The human IEC lines HT-29 and Caco-2 were used to study the effect of hyperosmolarity on the IEC inflammatory response. Exposure of IECs to hyperosmolarity triggered expression of the proinflammatory chemokine interleukin (IL)-8 both at the secreted protein and mRNA levels. In addition, hyperosmotic stimulation induced the release of another chemokine, GRO-alpha. These effects were because of activation of the transcription factor, nuclear factor (NF)-kappaB, because hyperosmolarity stimulated both NF-kappaB DNA binding and NF-kappaB-dependent transcriptional activity. Hyperosmolarity activated both p38 and p42/44 mitogen-activated protein kinases, which effect contributed to hyperosmolarity-stimulated IL-8 production, because p38 and p42/44 inhibition prevented the hyperosmolarity-induced increase in IL-8 production. In addition, the proinflammatory effects of hyperosmolarity were, in a large part, mediated by activation of Na(+)/H(+) exchangers, because selective blockade of Na(+)/H(+) exchangers prevented the hyperosmolarity-induced IEC inflammatory response. In summary, hyperosmolarity stimulates IEC IL-8 production, which effect may contribute to the maintenance of inflammation in inflammatory bowel disease.
 ...
PMID:Hyperosmotic stress induces nuclear factor-kappaB activation and interleukin-8 production in human intestinal epithelial cells. 1221 27

Conventional treatment of chronic inflammatory disorders, including inflammatory bowel diseases, employs broad-range anti-inflammatory drugs. In order to reduce the side-effects and increase the efficacy of treatment, several strategies have been developed in the last decade to interfere with intercellular and intracellular inflammatory signalling processes. The highly conserved mitogen-activated protein kinase pathways regulate most cellular processes, particularly defence mechanisms such as stress reactions and inflammation. In this review, we provide an overview of the current knowledge of the specificity and interconnection of mitogen-activated protein kinase pathways, their functions in the gut immune system and published and ongoing studies on the role of mitogen-activated protein kinases in inflammatory bowel disease. The development of mitogen-activated protein kinase inhibitors and their use for the therapy of inflammatory disorders is a paradigm of the successful bridging of the gap between basic research and clinical practice.
 ...
PMID:Review article: mitogen-activated protein kinases in chronic intestinal inflammation - targeting ancient pathways to treat modern diseases. 1284 23

Interleukin-1 (IL-1) plays a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). IL-1 action is regulated in part by its naturally occurring inhibitor, the IL-1 receptor antagonist (IL-1Ra). Four splice variants of IL-1Ra gene product have been described, one secreted (sIL-1Ra) and three intracellular (icIL-1Ra1, 2, 3). Although sIL-1Ra and icIL-1Ra1 bind to type I IL-1 receptor with equal affinity, icIL-1Ra1 may carry out unique functions inside cells. The goal of this study was to determine the role of icIL-1Ra1 in regulation of cytokine-induced IL-6 and IL-8 production in Caco-2 intestinal epithelial cells. icIL-1Ra1 inhibited IL-1-induced IL-6 and IL-8 production. IL-1 activated all three mitogen-activated protein (MAP) kinase family members: p38 MAP kinase, extracellular-regulated kinases (ERK), and c-Jun amino-terminal kinases (JNK). Specific inhibitors of each MAP kinase pathway decreased IL-1-induced IL-6 and IL-8 production. Overexpression of icIL-1Ra1 inhibited p38 MAP kinase phosphorylation, but had no effect on ERK and JNK phosphorylation. In addition, icIL-1Ra1 inhibited nuclear translocation of NF-kappaB after IL-1 stimulation. In conclusion, these data indicate that icIL-1Ra1, acting in the cytoplasm of Caco-2 cells, decreased IL-1-induced IL-6 and IL-8 production. This intracellular anti-inflammatory activity of icIL-1Ra1 was mediated through inhibition of p38 MAP kinase and NF-kappaB signal transduction pathways.
 ...
PMID:Intracellular IL-1Ra type 1 inhibits IL-1-induced IL-6 and IL-8 production in Caco-2 intestinal epithelial cells through inhibition of p38 mitogen-activated protein kinase and NF-kappaB pathways. 1290 52

Recent controlled and uncontrolled trial data in inflammatory bowel disease have suggested several new avenues of possible therapies and refined our understanding of the uses and selectiveness of anti-tumor necrosis factor (TNF)-based therapies. Infliximab remains the only proven effective anti-TNF therapy, whereas others have proven ineffective (etanercept, CDP-571) or of limited utility (thalidomide, CDP-870). A Crohn's disease Clinical trial Evaluating infliximab in a New long-term Treatment regimen (ACCENT I) and ACCENT II trials supported the strategy of using 5 to 10 mg/kg of infliximab on an every 8-week basis for maintenance of remission, although in clinical practice many physicians take variable approaches to maintenance of remission dosing schedules. On the other hand, no controlled trial data to date have supported the use of infliximab in ulcerative colitis. Therapies utilizing novel mechanistic approaches, such as hematopoietic growth factors, mitogen-activated protein (MAP)-kinase inhibition, and peroxisome proliferator activated receptor gamma ligand receptor binding have shown promise in small uncontrolled trials and await confirmation of their utility in randomized, placebo-controlled trials. Newer biologic (natalizumab) or cytokine-based therapies (monoclonal antibody to interleukin-6) have shown preliminary evidence of efficacy in controlled trials, but neither have yet been approved by the US Food and Drug Administration and, therefore, have not been commercialized. However, tacrolimus, a potent calcineurin inhibitor and inhibitor of interleukin-2 expression, has shown efficacy in Crohn's disease, albeit at the cost of substantial potential toxicity.
 ...
PMID:Newer Therapies for Inflammatory Bowel Disease. 1514 78

Interleukin (IL)-8 plays a central role in the initiation and maintenance of inflammatory responses in the inflammatory bowel disease. The proinflammatory cytokine-mediated production of IL-8 requires activation of various kinases, which leads to the IkappaB degradation and NF-kappaB activation. In this study, we investigated the role of luteolin, a major flavonoid of Lonicera japonica, on TNF-alpha-induced IL-8 production in human colonic epithelial cells. HT29 cells were stimulated with TNF-alpha in the presence or absence of luteolin. IL-8 production was measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, and the mitogen-activated protein kinases (MAPKs) activation and IkappaB degradation were determined by Western blot analysis. NF-kappaB activation was assessed by the electrophoretic motility shift assay (EMSA). Luteolin suppressed TNF-alpha-induced IL-8 production in dose-dependent manner. In addition, luteolin inhibited TNF-alpha-induced phosphorylation of p38 MAPK and extracellular-regulated kinases (ERK), IkappaB degradation, and NF-kappaB activation. These results suggest that luteolin has the inhibitory effects on TNF-alpha-induced IL-8 production in the intestinal epithelial cells through blockade in the phosphorylation of MAPKs, following IkappaB degradation and NF-kappaB activation.
 ...
PMID:Inhibitory effect of luteolin on TNF-alpha-induced IL-8 production in human colon epithelial cells. 1558 82

Interleukin (IL)-8 plays a central role in the initiation and maintenance of inflammatory responses in the inflammatory bowel disease. The proinflammatory cytokine-mediated production of IL-8 requires activation of various kinases, which leads to the I kappa B degradation and NF-kappa B activation. We investigated the role of 18 beta-glycyrrhetinic acid (GA), a saponin isolated from licorice roots, on TNF-alpha-induced IL-8 production in human colonic epithelial cells. HT29 cells were stimulated with TNF-alpha in the presence or absence of GA (1, 5 or 10 microM). IL-8 production was measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase-polymerase chain reaction analysis, and the mitogen-activated protein kinases (MAPKs) activation and I kappa B alpha degradation were determined by Western blot analysis. GA suppressed TNF-alpha-induced IL-8 production in a concentration-dependent manner. In addition, GA inhibited TNF-alpha-induced phosphorylation of p38 MAPK and extracellular-regulated kinases (ERK), I kappa B alpha degradation, and NF-kappa B activation. These results suggest that GA has the inhibitory effects on TNF-alpha-induced IL-8 production in the intestinal epithelial cells through blockade in the phosphorylation of MAPKs, following I kappa B alpha degradation and NF-kappa B activation.
 ...
PMID:Inhibition of interleukin-8 production in the human colonic epithelial cell line HT-29 by 18 beta-glycyrrhetinic acid. 1587 Sep 3

The p38 mitogen-activated protein (MAP) kinase has been implicated in the proinflammatory cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease. To develop a new drug for RA, we synthesized a novel series of 4-phenyl-5-pyridyl-1,3-thiazoles and evaluated their inhibition of p38 MAP kinase, lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells in vitro, and LPS-induced TNF-alpha production in vivo in mice. During the course of the study, we found that these compounds risk the inhibition of cytochrome P450 (CYP) isoforms by coordination of the 4-pyridyl nitrogen with heme iron. We therefore investigated the effects of substitution at the 2-position of the pyridyl ring on the inhibitory activity of p38 MAP kinase and CYPs in more detail. As a result, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (8h, TAK-715) exhibited potent inhibitory activity in these assays (inhibition of p38alpha, IC50 = 7.1 nM; LPS-stimulated release of TNF-alpha from THP-1, IC50 = 48 nM; LPS-induced TNF-alpha production in mice, 87.6% inhibition at 10 mg/kg, po) and no inhibitory activity for major CYPs, including CYP3A4. This compound also showed good bioavailability in mice and rats and significant efficacy in a rat adjuvant-induced arthritis model. Compound 8h was selected as a clinical candidate and is now under clinical investigation for the treatment of RA.
 ...
PMID:Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent. 1616

p38 mitogen-activated protein kinases (MAPKs) are activated primarily in response to inflammatory cytokines and cellular stress, and inhibitors which target the p38alpha and p38beta MAPKs have shown potential for the treatment of inflammatory disease. Here we report the generation and initial characterization of a knockout of the p38beta (MAPK11) gene. p38beta-/- mice were viable and exhibited no apparent health problems. The expression and activation of p38alpha, ERK1/2, and JNK in response to cellular stress was normal in embryonic fibroblasts from p38beta-/- mice, as was the activation of p38-activated kinases MAPKAP-K2 and MSK1. The transcription of p38-dependent immediate-early genes was also not affected by the knockout of p38beta, suggesting that p38alpha is the predominant isoform involved in these processes. The p38beta-/- mice also showed normal T-cell development. Lipopolysaccharide-induced cytokine production was also normal in the p38beta-/- mice. As p38 is activated by tumor necrosis factor, the p38beta-/- mice were crossed onto a TNFDeltaARE mouse line. These mice overexpress tumor necrosis factor, which results in development symptoms similar to rheumatoid arthritis and inflammatory bowel disease. The progression of these diseases was not however moderated by knockout of p38beta. Together these results suggest that p38alpha, and not p38beta, is the major p38 isoform involved in the immune response and that it would not be necessary to retain activity against p38beta during the development of p38 inhibitors.
 ...
PMID:Generation and characterization of p38beta (MAPK11) gene-targeted mice. 1628 58


1 2 3 4 Next >>