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

T helper (Th) 2-type cytokines play a dominant role in allergic inflammation. Accumulating evidence suggests that Th1-type cytokines antagonize Th2-type cytokine responses; however, recent studies demonstrate that Th1 cytokines might enhance Th2 immune responses. We examined whether interferon (IFN)-gamma, a representative Th1 cytokine, modifies the effector functions of human eosinophils stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-5. GM-CSF and IL-5 have significant functional homology, and contribute to the regulation of Th2 immunity. After the pretreatment of eosinophils with IFN-gamma, GM-CSF- or IL-5-induced eosinophil functions were examined, including superoxide anion generation, degranulation, adhesion, expression of GM-CSF receptor (R), IL-5R, or CD11b, and phosphorylation of intracellular signaling molecules. Superoxide anion generation was measured using the cytochrome c reduction method. Degranulation and cell adhesion were evaluated based on eosinophil-derived neurotoxin (EDN) contents in supernatants or adherent cells. Phosphorylation of signaling molecules was analyzed using a multiplex beads array system. Preincubation with IFN-gamma resulted in enhanced GM-CSF- or IL-5-induced superoxide anion generation and degranulation of human eosinophils, whereas stimulus-induced eosinophil adhesion was unaffected. In addition, IFN-gamma did not influence the expression of GM-CSFR, IL-5R, and CD11b. Furthermore, IFN-gamma upregulated GM-CSF- or IL-5-induced phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and activating transcription factor (ATF)-2. Finally, we confirmed that MAPK inhibitors blocked the enhancement of stimuli-induced superoxide anion generation of IFN-gamma treated eosinophils. In conclusion, IFN-gamma might upregulate ERK, p38, or JNK/ATF-2 phosphorylation induced by GM-CSF or IL-5, leading to enhanced cytokine-induced eosinophil superoxide generation and degranulation.
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PMID:Interferon-gamma enhances human eosinophil effector functions induced by granulocyte-macrophage colony-stimulating factor or interleukin-5. 1844 Jun 51

While Interleukin-5 (IL-5) is initially identified by its ability to support the growth and differentiation of activated B cells, overexpression of IL-5 significantly increases eosinophil numbers and antibody levels predominantly from an expanded population of B-1 cells in vivo. Conversely, mice lacking a functional gene for IL-5 or IL-5 receptor alpha chain (IL-5Ralpha) display a number of developmental and functional impairments in B cell and eosinophil lineages. In addition to the JAK-STAT and Btk pathway, the Ras-extracellular signal-regulated kinase (ERK) signals are important for IL-5-dependent cell survival. IL-5 critically regulates expression of genes involved in cell survival, IgH switch recombination, maturation in B cells and genes required for growth, survival, and effector function of eosinophils. IL-5Ralpha expression in B cells, but not in eosinophils is regulated by Oct-2. Eosinophilia is associated with a wide variety of conditions, including asthma and atopic diseases, helminth infections, drug hypersensitivity, and neoplastic disorders. In humans, the biologic effects of IL-5 are best characterized for eosinophils. The Sprouty-related Ena/VASP homology 1-domain containing protein (Spred)-1 negatively controls eosinophil numbers and functions by modulating IL-5 signaling in allergic asthma. We will emphasize that IL-5 plays a pivotal role in the innate and acquired immune response and eosinophilia.
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PMID:IL-5 and eosinophilia. 1851 Dec 50

GATA-3 is a transcription factor that is specifically expressed in T helper 2 (Th2) cells and plays a critical role in the differentiation of Th2 cells from uncommitted CD4+ lymphocytes. In addition GATA-3 is essential for the gene expression of the cytokines IL-4, IL-5 and IL-13 that mediate allergic inflammation. In human T lymphocytes GATA-3 is normally localized to the cytoplasm, but on activation by antigen-presenting cells via the T cell receptor (CD3) and co-stimulatory receptor CD28 GATA-3 is phosphorylated by p38 MAP kinase and translocates to the nucleus via the nuclear import protein importin-alpha. Corticosteroids bound to glucocorticoid receptors inhibit GATA-3 function by competing for nuclear entry via importin-alpha and also by inhibiting p38 MAP kinase through the induction of MAP kinase phosphatase-1. GATA-3 is inhibited by the Th1 master regulatory transcription T-bet but in turn inhibits STAT-4 and thus T-bet so that Th2 polarization is maintained. Since GATA-3 appears to be a critical transcription factor for allergic inflammation it is an obvious target for inhibition. However, direct inhibition by inhaled specific oligonucleotides or interference RNA is not yet possible. Corticosteroids act as indirect inhibitors and in patients with corticosteroid resistance p38 MAP kinase inhibitors may also prove to be useful in the future.
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PMID:Role of GATA-3 in allergic diseases. 1869 Oct 59

The differentiation of naive CD4 T cells into Th2 cells requires the T cell receptor-mediated activation of the ERK MAPK cascade. Little is known, however, in regard to how the ERK MAPK cascade regulates Th2 cell differentiation. We herein identified Gfi1 (growth factor independent-1) as a downstream target of the ERK MAPK cascade for Th2 cell differentiation. In the absence of Gfi1, interleukin-5 production and the change of histone modification at the interleukin-5 gene locus were severely impaired. Furthermore, the interferon gamma gene showed a striking activation in the Gfi1(-/-) Th2 cells. An enhanced ubiquitin/proteasome-dependent degradation of GATA3 protein was observed in Gfi1(-/-) Th2 cells, and the overexpression of GATA3 eliminated the defect of Th2 cell function in Gfi1-deficient Th2 cells. These data suggest that the T cell receptor-mediated induction of Gfi1 controls Th2 cell differentiation through the regulation of GATA3 protein stability.
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PMID:Gfi1-mediated stabilization of GATA3 protein is required for Th2 cell differentiation. 1870 59

Here, we examined the functional involvement of heterotrimeric G-proteins in TCR-induced immune responses. TCR/CD3 crosslinking resulted in activation of both Galphaq and Galphas, but not Galphai-2. Targeting of Galphas, Galphai-2 and Galphaq using siRNA demonstrated a specific role of Galphaq in TCR signaling. Jurkat TAg T cells with Galphaq knockdown displayed reduced activation of Lck and LAT phosphorylation, but paradoxically showed sustained ERK1/2 phosphorylation and increased NFAT-AP-1-reporter activity implicating Galphaq in the negative control of downstream signaling and IL-2-promoter activity. Primary T cells isolated from Galphaq-deficient mice had a similar TCR signaling response with reduced proximal LAT phosphorylation, sustained ERK1/2 phosphorylation and augmented immune responses including increased secretion of IL-2, IL-5, IL-12 and TNF-alpha. The effects on NFAT-AP-1-reporter activity were sensitive to the Src family kinase inhibitor PP2 and were reversed by transient expression of constitutively active Lck. Furthermore, expression of constitutively active Galphaq Q209L elevated Lck activity and Zap-70 phosphorylation. Together these data argue for a role of Galphaq in the fine-tuning of proximal TCR signals at the level of Lck and a negative regulatory role of Galphaq in transcriptional activation of cytokine responses.
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PMID:The heterotrimeric G-protein alpha-subunit Galphaq regulates TCR-mediated immune responses through an Lck-dependent pathway. 1899 Dec 94

In the present study, we found that (-)-epigallocatechin-3-gallate (EGCG) significantly up-regulated the mRNA expression of the Th1/Th2 cytokines including IL-2, IFN-gamma, IL-5 and IL-13 in Jurkat T cells. The EGCG-induced mRNA up-regulation of IL-2 and IL-5 was predominantly affected by the extracellular signal-regulated protein kinase (ERK) signalling, whereas IL-13 gene expression, the most responsive to the EGCG treatment, was dependent on neither ERK nor c-jun NH(2)-terminal kinase (JNK) signalling. IFN-gamma gene expression was partially mitigated by both inhibitors of the ERK and JNK pathways. Furthermore, catalase significantly attenuated the intracellular peroxide production, phosphorylation of ERK and JNK, and all cytokine gene expressions induced by EGCG. In addition, physiologically relevant concentrations of both EGCG and H(2)O(2)-induced up-regulation of IL-5 gene expression. Our findings provide biological evidence that EGCG induces Th1/Th2 cytokine mRNA expression via H(2)O(2) production followed by activation of ERK or JNK in Jurkat T cells.
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PMID:(-)-Epigallocatechin-3-gallate induces up-regulation of Th1 and Th2 cytokine genes in Jurkat T cells. 1913 25

Resistin-like molecule alpha (Relm-alpha) is a secreted cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-beta, and Relm-gamma. Resistin was initially defined based on its insulin resistance activity, but the family members are highly up-regulated in various inflammatory states, especially those involving intestinal inflammation. In this study, we report the role of Relm-alpha at baseline and following an experimental model of colitis. Relm-alpha was readily detected in the serum at baseline (4-5 ng/ml), and its level was regulated by energy uptake. Retnla(-/-) mice had decreased baseline circulating leptin levels, but displayed normal glucose, glucose clearance, and insulin levels. Following exposure to the oral innate trigger dextran sodium sulfate (DSS), a nonredundant proinflammatory role for Relm-alpha was uncovered as Retnla(-/-) mice were markedly protected from DSS-induced disease activity and histopathological features. Relm-alpha regulated eosinophil-directed cytokines (e.g., IL-5, CCL11/eotaxin-1, and CCL5/RANTES) and IL-17 ex vivo. Consistently, DSS-treated Retnla(-/-) mice displayed substantially decreased eosinophil accumulation and decreased phosphorylation of NF-kappaB, ERK1/2, and p38 in macrophages and eosinophils. Following DSS exposure, serum level of Relm-alpha was up-regulated, and DSS-treated Retnla(-/-) mice were markedly protected from hyperglycemia induced by glucose injection independent of changes in insulin levels. Retnla(-/-) mice were protected from increases in gut hormone serum levels of gastric inhibitory polypeptide and peptide YY that were induced following DSS treatment. These findings demonstrate a central proinflammatory role for Relm-alpha in the regulation of colonic inflammation and a novel link between colonic injury, glucose tolerance, and energy intake.
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PMID:Resistin-like molecule alpha decreases glucose tolerance during intestinal inflammation. 1920 90

Leuconostoc citreum (L. citreum) HJ-P4 (KACC 91035) is one of the major predominant species in kimchi fermentation in Korea. The purpose of the present study was to test the immunomodulatory capacity of L. citreum to modulate the IgE-mediated allergic response and to examine the involvement of NF-kappaB and MAPK in IL-12 production in macrophages. Balb/c mice were sensitized with OVA/alum and oral administration of L. citreum to the mice began before or after the OVA sensitization. Protein and mRNA expression of Th1 cytokines in splenocytes by L. citreum in vitro was measured. The role of NF-kappaB and MAPK such as p38, ERK1/2 and JNK in L. citreum-induced IL-12 was investigated in peritoneal macrophages and RAW264.7 cell lines. L. citreum inhibited the serum levels of total IgE, IgG1 and IgG2a altogether and increased OVA-specific IFN-gamma production in splenocytes from pre- and post-sensitized animals. However, the downregulation of IL-4 and IL-5 production was observed only in the pre-sensitization group. The ability of L. citreum to stimulate IFN-gamma was dependent on its induction of IL-12. NF-kappaB, p38 and JNK were mainly involved in L. citreum-induced IL-12 production. In conclusion, the current study demonstrated that L. citreum is able to regulate serum IgE generation at the induction and effector phases of allergic response through overall control over antibody production and that its involvement of IL-12 production was mediated through NF-kappaB and p38/JNK. Taken together, the use of L. citreum can be useful in preventing the development and progression of IgE production.
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PMID:Leuconostoc citreum HJ-P4 (KACC 91035) regulates immunoglobulin E in an ovalbumin-induced allergy model and induces interleukin-12 through nuclear factor-kappa B and p38/c-Jun N-terminal kinases signaling in macrophages. 1949 1

IL-5 was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells, at least in mice. Concurrently, IL-5 was recognized as the major maturation and differentiation factor for eosinophils in mice and humans. Over-expression of IL-5 significantly increases eosinophil numbers and antibody levels in vivo. Conversely, mice lacking a functional gene for IL-5 or the IL-5 receptor alpha chain (IL-5Ralpha) display a number of developmental and functional impairments in B-cell and eosinophil lineages. In addition to the Janus kinase-signal transducer and activator of transcription pathway, the tyrosine kinases Lyn and Btk (Bruton agammaglobulinemia tyrosine kinase) are involved, and Ras GTPase-extracellular signal-regulated kinase (Ras-ERK) signals are important for IL-5-dependent cell proliferation and survival. IL-5 critically regulates expression of genes involved in proliferation, cell survival and maturation and effector functions of B cells and eosinophils. Thus, IL-5 plays a pivotal role in innate and acquired immune responses and eosinophilia. In humans, the biologic effects of IL-5 are best characterized for eosinophils. The recent expansion in our understanding of the mechanisms of eosinophil development and activation in the context of IL-5 has led to advances in therapeutic options. A new therapy currently in clinical trials uses humanized mAbs against IL-5 or the IL-5R.
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PMID:IL-5- and eosinophil-mediated inflammation: from discovery to therapy. 1981 37

Clinical and experimental studies have established eosinophilia as a sign of allergic disorders. Activation of eosinophils in the airways is believed to cause epithelial tissue injury, contraction of airway smooth muscle and increased bronchial responsiveness. As part of the search for new antiasthmatic agents produced by medicinal plants, the effects of 270 standardized medicinal plant extracts on cytokine-activated A549 human lung epithelial cells were evaluated. After several rounds of activity-guided screening, the new natural compound, 1H,8H-Pyrano[3,4-c]pyran-1,8-dione (PPY), was isolated from Vitex rotundifolia L. To elucidate the mechanism by which the anti-asthmatic responses of PPY occurred in vitro, lung epithelial cells (A549 cell) were stimulated with TNF-alpha, IL-4 and IL-1beta to induce the expression of chemokines and adhesion molecules involved in eosinophil chemotaxis. PPY treatments reduced the expression of eotaxin, IL-8, IL-16 and VCAM-1 mRNA significantly. Additionally, PPY reduced eotaxin secretion in a dose-dependent manner and significantly inhibited eosinophil migration toward A549 medium. In addition, PPY treatment suppressed the phosphorylation of p65 and ERK1/2, suggesting that it can inhibit the MAPK/NF-KB pathway. To clarify the anti-inflammatory and antiasthmatic effects of PPY in vivo, we examined the influence of PPY on the development of pulmonary eosinophilic inflammation in a murine model of asthma. To accomplish this, mice were sensitized and challenged with ovalbumin (OVA) and then examined for the following typical asthmatic reactions: an increase in the number of eosinophils in BALF; the presence of Th2 cytokines such as IL-4 and IL-5 in the BALF; the presence of allergen-specific IgE in the serum; and a marked influx of inflammatory cells into the lung. Taken together, our results revealed that PPY exerts profound inhibitory effects on the accumulation of eosinophils into the airways while reducing the levels of IL-4, IL-5, and IL-13 in the BALF. Therefore, these results suggest that PPY may be useful as a new therapeutic drug for the treatment of allergic asthma.
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PMID:A new compound, 1H,8H-pyrano[3,4-c]pyran-1,8-dione, suppresses airway epithelial cell inflammatory responses in a murine model of asthma. 1982 76


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