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)

The family of mammalian chitinases includes members both with and without glycohydrolase enzymatic activity against chitin, a polymer of N-acetylglucosamine. Chitin is the structural component of fungi, crustaceans, insects and parasitic nematodes, but is completely absent in mammals. Exposure to antigens containing chitin- or chitin-like structures sometimes induces strong T helper type-I responses in mammals, which may be associated with the induction of mammalian chitinases. Chitinase 3-like-1 (CHI3L1), a member of the mammalian chitinase family, is induced specifically during the course of inflammation in such disorders as inflammatory bowel disease, hepatitis and asthma. In addition, CHI3L1 is expressed and secreted by several types of solid tumors including glioblastoma, colon cancer, breast cancer and malignant melanoma. Although the exact function of CHI3L1 in inflammation and cancer is still largely unknown, CHI3L1 plays a pivotal role in exacerbating the inflammatory processes and in promoting angiogenesis and remodeling of the extracellular matrix. CHI3L1 may be highly involved in the chronic engagement of inflammation which potentiates development of epithelial tumorigenesis presumably by activating the mitogen-activated protein kinase and the protein kinase B signaling pathways. Anti-CHI3L1 antibodies or pan-chitinase inhibitors may have the potential to suppress CHI3L1-mediated chronic inflammation and the subsequent carcinogenic change in epithelial cells.
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PMID:Potential role of chitinase 3-like-1 in inflammation-associated carcinogenic changes of epithelial cells. 1990 31

Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is an important target in the treatment of inflammatory bowel disease (IBD). Recently, treatment of IBD with an antibody to alpha4beta7-integrin, a ligand for MAdCAM-1, has been an intense focus of research. Our aim was to clarify the mechanism by which MAdCAM-1 is regulated via angiotensin II type 1 receptor (AT1R), and to verify if AT1R might be a novel target for IBD treatment. The role of AT1R in the expression of MAdCAM-1 in SVEC (a murine high endothelial venule cell) and MJC-1 (a mouse colonic endothelial cell) was examined following cytokine stimulation. We further evaluated the effect of AT1R on the pathogenesis of immune-mediated colitis using AT1R-deficient (AT1R-/-) mice and a selective AT1R blocker. AT1R blocker significantly suppressed MAdCAM-1 expression induced by TNF-alpha, but did not inhibit phosphorylation of p38 MAPK or of IkappaB that modulate MAdCAM-1 expression. However, NF-kappaB translocation into the nucleus was inhibited by these treatments. In a murine colitis model induced by dextran sulfate sodium, the degree of colitis, judged by body weight loss, histological damage, and the disease activity index, was much milder in AT1R-/- than in wild-type mice. The expression of MAdCAM-1 was also significantly lower in AT1R-/- than in wild-type mice. These results suggest that AT1R regulates the expression of MAdCAM-1 under colonic inflammatory conditions through regulation of the translocation of NF-kappaB into the nucleus. Furthermore, inhibition of AT1R ameliorates colitis in a mouse colitis model. Therefore, AT1R might be one of new therapeutic target of IBD via regulation of MAdCAM-1.
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PMID:Blockage of angiotensin II type 1 receptor regulates TNF-alpha-induced MAdCAM-1 expression via inhibition of NF-kappaB translocation to the nucleus and ameliorates colitis. 1994 29

Inflammatory bowel disease and arthritis are associated with contact activation that results in cleavage of kininogen to form high molecular weight kininogen (HKa) and bradykinin. We have previously demonstrated that HKa can stimulate inflammatory cytokine and chemokine secretion from human monocytes. We now show that HKa can upregulate tissue factor antigen and procoagulant activity on human monocytes as a function of time (1-4 h) and HKa concentration (75-900 nM). The amino acid sequence responsible to block HKa effects is G440-H455. The HKa receptor macrophage-1 (Mac-1; CD11b18) is the binding site as shown by inhibition by a monoclonal antibody to CD11b/18. Chemical inhibitors of JNK, ERK, and p38 signaling pathways block cell signaling, as does an inhibitor to the transcription factor NF-kappaB. A combination of monoclonal antibodies to TNF-alpha and IL-1beta but neither alone inhibited the HKa induction of tissue factor. These results suggest that HKa mimics LPS by triggering a paracrine pathway in monocytes that depends on TNF-alpha and IL-1beta. Antibodies to kininogen or peptidomimetics might be a useful and safe therapy in inflammatory diseases or sepsis involving cytokines.
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PMID:Upregulation of tissue factor in monocytes by cleaved high molecular weight kininogen is dependent on TNF-alpha and IL-1beta. 1996 52

Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC). It is thought to be caused by genetic, abnormal immune response of the intestinal immune system and dysfunction of intestinal mucosal barrier against enteric bacteria. Mutational genes can affect the development of IBDs via certain signaling pathways. The abnormal signaling pathways play an important role in the inflammatory process and can lead to dysregulation of the inflammatory response and are crucial in the pathogenesis of IBDs. The signaling pathways mainly include P38 MAPK, JNK MAPK, PI3K/Akt, NF-kappaB signaling pathways. Intestinal microorganisms play a key role in the initiation and maintenance of disease. Disorders of signaling pathways including TLR, NF-kappaB can act on the intestinal barrier, and cause uninhibitedly release of effector T cells which are the central cells mediating inflammation in CD. This review highlights relevant patents and a new insight of signaling pathways associated with IBDs will help to develop better therapeutic approaches.
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PMID:Signaling pathways associated with inflammatory bowel disease. 2000 99

Recent studies have demonstrated that the complement system participates in the regulation of T cell functions. To address the local biosynthesis of complement components in inflammatory bowel disease (IBD) mucosa, we investigated C3 and interleukin (IL)-17 mRNA expression in mucosal samples obtained from patients with IBD. The molecular mechanisms underlying C3 induction were investigated in human colonic subepithelial myofibroblasts (SEMFs). IL-17 and C3 mRNA expressions in the IBD mucosa were evaluated by real-time polymerase chain reaction. The C3 levels in the supernatant were determined by enzyme-linked immunosorbent assay. IL-17 and C3 mRNA expressions were elevated significantly in the active lesions from ulcerative colitis (UC) and Crohn's disease (CD) patients. There was a significant positive correlation between IL-17 and C3 mRNA expression in the IBD mucosa. IL-17 stimulated a dose- and time-dependent increase in C3 mRNA expression and C3 secretion in colonic SEMFs. The C3 molecules secreted by colonic SEMFs were a 115-kDa alpha-chain linked to a 70-kDa beta-chain by disulphide bonds, which was identical to serum C3. The IL-17-induced C3 mRNA expression was blocked by p42/44 mitogen-activated protein kinase (MAPK) inhibitors (PD98059 and U0216) and a p38 MAPK inhibitor (SB203580). Furthermore, IL-17-induced C3 mRNA expression was inhibited by an adenovirus containing a stable mutant form of I kappaB alpha. C3 and IL-17 mRNA expressions are enhanced, with a strong correlation, in the inflamed mucosa of IBD patients. Part of these clinical findings was considered to be mediated by the colonic SEMF response to IL-17.
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PMID:The increased mucosal mRNA expressions of complement C3 and interleukin-17 in inflammatory bowel disease. 2008 77

Luteolin (3',4',5,7-tetrahydroxylflavone) is a plant flavonoid and pharmacologically active agent that has been isolated from several plant species. In the present study, the effect of luteolin from the flowers of Lonicera japonica on phorbol 12-myristate 13-acetate (PMA) plus A23187-induced mast cell activation was examined. Luteolin significantly inhibited the induction of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-8, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) by PMA plus A23187. Moreover, luteolin attenuated cyclooxygenase (COX)-2 expression and intracellular Ca2+ levels. In activated HMC-1 cells, the phosphorylation of extra-signal response kinase (ERK 1/2) and c-jun N-terminal Kinase (JNK 1/2), but not p38 mitogen-activated protein kinase (p38 MAPK) were decreased by treatment of the cells with luteolin. Luteolin inhibited PMA plus A23187-induced nuclear factor (NF)-kappaB activation, IkappaB degradation, and luciferase activity. Furthermore, luteolin suppressed the expression of TNF-alpha, IL-8, IL-6, GM-CSF, and COX-2 through a decrease in the intracellular Ca2+ levels, and also showed a suppression of the ERK 1/2, JNK 1/2, and NF-kappaB activation. These results indicated that luteolin from the flowers of Lonicera japonica exerted a regulatory effect on mast cell-mediated inflammatory diseases, such as RA, allergy disease and IBD.
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PMID:Luteolin isolated from the flowers of Lonicera japonica suppresses inflammatory mediator release by blocking NF-kappaB and MAPKs activation pathways in HMC-1 cells. 2011 Aug 98

REG4, the latest member of the regenerating gene family, is overexpressed in inflammatory bowel diseases and gastrointestinal carcinomas. To date, its pathophysiologic role has not been well established. Using HT-29 models, we previously identified REG4 as being overexpressed in colorectal tumor cells displaying a drug-resistance phenotype; some also displayed invasive properties. Thus, we investigated the potential functions of REG4 in biological processes involved in colorectal tumor progression such as cell proliferation, migration and invasion. Colon cancer cells secreting REG4 (HT29-5M21, HT29-5F7 and HT29/REG4-8) or not (HT-29, HT29/CT1 and Caco-2/TC7) were used to analyze the autocrine and paracrine effects of REG4. REG4 was continuously secreted into the culture medium of colon cancer cells. REG4 stimulated cell growth in a paracrine manner after 24 h of treatment. Notably, REG4 promoted migration and invasion of tumor cells in both an autocrine and paracrine manner, and these effects were significantly decreased by concomitant treatment with an anti-REG4 antibody. Using pharmacological inhibitors, we showed that PI3K/Akt, PKAs, PKCs and Rho-like GTPases, but not MAPK, are involved in REG4 invasion signals. In addition, REG4 expression was found to be increased in tissues harboring proliferation and migration properties such as the developing intestine and tissues from inflammatory bowel disease, hyperplastic polyps, adenoma and colorectal cancers. In various situations, REG4 expression was not confined to proliferating cells, regenerating cells or cells of the invasive front of metastatic tumors, suggesting that extracellular REG4 may act on epithelial cells in a paracrine manner. Altogether, our results indicate that REG4 is a multifunctional secreted protein which acts on colorectal cancer cells in an autocrine and paracrine manner. According to its biological functions and tissue expression, REG4 may play an important role in the development and progression of colorectal cancer, as well as in intestinal morphogenesis and epithelium restitution.
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PMID:REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells. 2012 89

The tumor necrosis factor-alpha (TNF-alpha) cytokine, secreted by activated monocytes/macrophages and T lymphocytes, is implicated in several diseases, including rheumatoid arthritis, chronic obstructive pulmonary disease, inflammatory bowel disease, and osteoporosis. Monocyte/macrophage production of TNF-alpha is largely driven by p38alpha mitogen-activated protein kinase (MAP kinase), an intracellular soluble serine-threonine kinase. p38alpha MAP kinase is activated by growth factors, cellular stresses, and cytokines such as TNF-alpha and interleukin-l (IL-I). The primary contribution of p38alpha activation to excess TNF-alpha in settings of both chronic and acute inflammation has instigated efforts to find inhibitors of this enzyme as possible therapies for associated disease states. Analogue design, synthesis, and structure-activity studies led to the identification of 5-tert-butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2-oxo-acetylamino}-benzamide (KR-003048) as a potent inhibitor of the p38 MAP kinase signaling pathway in vitro and in vivo. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide (LPS)-induced p38 activation and subsequent TNF-alpha release is described. KR-00348 was demonstrated to be a potent inhibitor of inflammatory cytokine production ex vivo in rat and human whole blood, and showed good oral bioavailability. Additionally, efficacy in mouse and rat models of acute and chronic inflammation was obtained. KR-003048 possessed therapeutic activity in acute models, demonstrating substantial inhibition of carrageenan-induced paw edema and in vivo LPS-induced TNF release at 30mg/kg p.o. Collagen-induced arthritis in mice was significantly inhibited by 10 and 30mg/kg doses of KR-003048. Evidence for disease-modifying activity in this model was indicated by histological evaluation of joints.
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PMID:KR-003048, a potent, orally active inhibitor of p38 mitogen-activated protein kinase. 2013 13

Tumor necrosis factor alpha (TNF-alpha) is a major inflammatory cytokine that plays an important role in the development of various inflammatory diseases. TNF-alpha has been considered as a potential therapeutic target for the treatment of chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. In this study, we report that cyclopropyl-{4-[4-(4-fluorophenyl)-2-piperidin-4-yl-thiazol-5-yl]pyrimidin-2-yl}amine (DBM1285) is a novel inhibitor of TNF-alpha production. DBM1285 concentration-dependently inhibited lipopolysaccharide (LPS)-induced TNF-alpha secretion in various cells of macrophage/monocyte lineage, including mouse bone marrow macrophages, THP-1 cells, and RAW 264.7 cells. However, LPS-induced mRNA expression of TNF-alpha was not affected by DBM1285 in these cells. Further studies demonstrated that the inhibitory effect of DBM1285 on TNF-alpha production might be mediated by post-transcriptional regulation through the modulation of the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) signaling pathway. We also confirmed that DBM1285 directly inhibits p38 MAPK enzymatic activity. In vivo administration of DBM1285 inhibited LPS-induced increase in the plasma level of TNF-alpha in mice. Whole-blood in vivo target inhibition assay also revealed that DBM1285 attenuates p38 MAPK activity after oral administration in mice. Moreover, DBM1285 suppressed zymosan-induced inflammation and adjuvant-induced arthritis in murine models. Collectively, these results suggest that DBM1285 inhibits TNF-alpha production, at least in part, by blocking the p38 MAPK/MK2 pathway. Furthermore, in vivo results suggest that DBM1285 might be a possible therapeutic candidate for the treatment of TNF-alpha-related chronic inflammatory diseases.
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PMID:DBM1285 suppresses tumor necrosis factor alpha production by blocking p38 mitogen-activated protein kinase/mitogen-activated protein kinase-activated protein kinase 2 signaling pathway. 2042 74

Chronic activation of immune responses, mediated by inflammatory mediators and involving different effector cells of the innate and acquired immune system characterizes autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and septic shock syndrome. MAPKs are crucial intracellular mediators of inflammation. MAPK inhibitors are attractive anti-inflammatory drugs, because they are capable of reducing the synthesis of inflammation mediators at multiple levels and are effective in blocking proinflammatory cytokine signaling. Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway converts cytokine signals into genomic responses regulating proliferation and differentiation of the immune cells. JAK inhibitors are a new class of immunomodulatory agents with immunosuppressive, anti-inflammatory and antiallergic properties. This review discusses the rationale behind current strategies of targeting MAPK and JAK/STAT signaling pathways, and the overall effects of signal transduction inhibitors in animal models of inflammatory disorders. Signal transduction inhibitors are small molecules that can be administered orally, and initial results of clinical trials have shown clinical benefits in patients with chronic inflammatory disorders.
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PMID:Targeting signaling pathways with small molecules to treat autoimmune disorders. 2047 90


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