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)

The mitogen-activated protein kinases, extracellular signal-regulated kinase (ERK), and p38, are activated in response to infectious agents and innate immune stimulators such as CpG DNA, and regulate the subsequent initiation and termination of immune responses. CpG DNA activates p38 and ERK with slightly different kinetics in monocytic cells. The present studies investigated the roles of these two key mitogen-activated protein kinases in regulating the CpG DNA-induced production of pro- and anti-inflammatory cytokines in the macrophage-like cell line RAW264.7. p38 activity was essential for the induction of both IL-10 and IL-12 expression by CpG DNA. In contrast, CpG DNA-mediated ERK activation was shown to suppress IL-12 production, but to be essential for the CpG DNA-induced IL-10 production. Studies using rIL-10 and IL-10 gene-deficient mice demonstrated that the inhibitory effect of ERK on CpG DNA-mediated IL-12 production is indirect, due to the role of ERK in mediating IL-10 production. These results demonstrate that ERK and p38 differentially regulate the production of pro- and anti-inflammatory cytokines in APCs that have been activated by CpG DNA. CpG DNA-induced p38 activity is required for the resulting innate immune activation. In contrast, ERK plays a central negative regulatory role in the CpG DNA-mediated Th1 type response by promoting production of the Th2 type cytokine, IL-10.
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PMID:Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. 1197 Oct 21

We examined the co-stimulatory activity of H4/ICOS on murine activated CD4(+) T cells and found that the cross-linking of H4/ICOS enhanced their proliferation, in addition to raising IFN-gamma, IL-4 and IL-10 production to levels comparable to those induced by CD28. However, IL-2 production was only marginally co-stimulated by H4/ICOS. This distinct pattern of lymphokine production appears to be induced by a specific intracellular signaling event. Compared with CD28, H4/ICOS dominantly elicited the Akt pathway via phosphatidylinositol 3-kinase. In addition, mitogen-activated protein kinase family kinases were activated in different ways by CD28 and H4/ICOS. The strong phosphorylation of p46 c-Jun N-terminal kinase was observed upon CD28 co-stimulation, but was less potently induced by H4/ICOS. The strain diversity in the induction of H4/ICOS was recognized. The expression of H4/ICOS on BALB/c activated CD4(+) T cells was >6-fold higher compared with C57BL/6 activated CD4(+) T cells. Furthermore, BALB/c activated CD4(+) T cells exhibited more T(h)2-deviated lymphokine production as compared with C57BL/6 activated CD4(+) T cells and signaling through H4/ICOS during the primary stimulation of naive CD4(+) T cells promoted the generation of T(h)2 cells. Thus, the difference in H4/ICOS expression on activated CD4(+) T cells, which is regulated among the mouse strains, may also regulate the polarization of T(h) cells.
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PMID:A co-stimulatory molecule on activated T cells, H4/ICOS, delivers specific signals in T(h) cells and regulates their responses. 1203 7

IL (interleukin)-22 is an IL-10-related cytokine; its main biological activity known thus far is the induction of acute phase reactants in liver and pancreas. IL-22 signals through a receptor that is composed of two chains from the class II cytokine receptor family: IL-22R (also called ZcytoR11/CRF2-9) and IL-10Rbeta (CRF2-4), which is also involved in IL-10 signaling. In this report, we analyzed the signal transduction pathways activated in response to IL-22 in a rat hepatoma cell line, H4IIE. We found that IL-22 induces activation of JAK1 and Tyk2 but not JAK2, as well as phosphorylation of STAT1, STAT3, and STAT5 on tyrosine residues, extending the similarities between IL-22 and IL-10. However our results unraveled some differences between IL-22 and IL-10 signaling. Using antibodies specific for the phosphorylated form of MEK1/2, ERK1/2, p90RSK, JNK, and p38 kinase, we showed that IL-22 activates the three major MAPK pathways. IL-22 also induced serine phosphorylation of STAT3 on Ser(727). This effect, which is not shared with IL-10, was only marginally affected by MEK1/2 inhibitors, indicating that other pathways might be involved. Finally, by overexpressing a STAT3 S727A mutant, we showed that serine phosphorylation is required to achieve maximum transactivation of a STAT responsive promoter upon IL-22 stimulation.
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PMID:Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. 1208

Mitogen-activated protein (MAP) kinases have been implicated as important mediators of the inflammatory response. Here we report that c-Jun NH(2)-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 MAP kinase activities are reprogrammed during the IL-6 induced macrophage-like differentiation of the murine myeloid M1 cell line. Moreover, p38 inhibition upregulates JNK and ERK activity in M1 cells and in thioglycollate-elicited peritoneal exudate macrophages. IL-6-induced M1 differentiation also induces expression of the anti-inflammatory cytokine IL-10, and p38 inhibition potentiates this increase in IL-10 expression in an ERK-dependent manner. Thus, we speculate that during inflammatory conditions in vivo macrophage p38 may regulate JNK and ERK activity and inhibit IL-10 expression. These data highlight the importance of p38 in the molecular mechanisms of macrophage function.
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PMID:Inhibition of the p38 pathway upregulates macrophage JNK and ERK activities, and the ERK, JNK, and p38 MAP kinase pathways are reprogrammed during differentiation of the murine myeloid M1 cell line. 1211 10

Superantigens are microbial proteins that induce massive activation, proliferation, and cytokine production by CD4+ T cells via specific Vbeta elements on the TCR. In this study we examine superantigen enhancement of Ag-specific CD4+ T cell activity for humoral B cell responses to T-dependent Ags BSA and HIV gp120 envelope, type I T-independent Ag LPS, and type II T-independent Ag pneumococcal polysaccharides. Injection of BSA followed by a combination of superantigens staphylococcal enterotoxin A and staphylococcal enterotoxin B (SEB) 7 days later enhanced the anti-BSA Ab response in mice approximately 4-fold as compared with mice given BSA alone. The anti-gp120 response was enhanced approximately 3-fold by superantigens. The type II T-independent Ag pneumococcal polysaccharide response was enhanced approximately 2.3-fold by superantigens, whereas no effect was observed on the response to the type I T-independent Ag LPS. The superantigen effect was completely blocked by the CD4+ T cell inhibitory cytokine IL-10. SEB-stimulated human CD4+ T cells were examined to determine the role of the mitogen-activated protein (MAP) kinase signal transduction pathway in superantigen activation of T cells. Inhibitors of the mitogen pathway of MAP kinase blocked SEB-induced proliferation and IFN-gamma production, while an inhibitor of the p38 stress pathway had no effect. Consistent with this, SEB activated extracellular signal-regulated kinase/MAP kinase as well as MAP kinase-interacting kinase, a kinase that phosphorylates eIF4E, which is an important component of the eukaryotic protein synthesis initiation complex. Both kinases were inhibited by IL-10. Thus, superantigens enhance humoral immunity via Ag-specific CD4+ T cells involving the stress-independent pathway of MAP kinase.
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PMID:Superantigen enhancement of specific immunity: antibody production and signaling pathways. 1221 4

Mast cells secrete multiple cytokines and play an important role in allergic inflammation. Although it is widely accepted that bacteria infection occasionally worsens allergic airway inflammation, the mechanism has not been defined. In this study, we show that LPS induced Th2-associated cytokine production such as IL-5, IL-10, and IL-13 from mast cells and also synergistically enhanced production of these cytokines induced by IgE cross-linking. LPS-mediated Th2-type cytokine production was abolished in mouse bone marrow-derived mast cells derived from C3H/HeJ mice, suggesting that Toll-like receptor 4 is essential for the cytokine production. Furthermore, we found that mitogen-activated protein kinases including extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 kinase were activated by LPS stimulation in bone marrow-derived mast cells. Inhibition of extracellular signal-regulated kinase activation has little effect on LPS-mediated cytokine production. In contrast, inhibition of c-Jun N-terminal kinase activation significantly suppressed both IL-10 and IL-13 expression at both mRNA and protein levels. Interestingly, although inhibition of p38 did not down-regulate the mRNA induction, it moderately decreased all three cytokine productions by LPS. These results indicate that LPS-mediated production of IL-5, IL-10, and IL-13 was distinctly regulated by mitogen-activated protein kinases. Our findings may indicate a clue to understanding the mechanisms of how bacteria infection worsens the clinical features of asthma.
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PMID:Th2 cytokine production from mast cells is directly induced by lipopolysaccharide and distinctly regulated by c-Jun N-terminal kinase and p38 pathways. 1224 75

Yeast expressed Hepatitis B surface antigen (rHBsAg) binds to monocytes through interaction with the LPS binding protein (LBP) and the LPS receptor CD14. Charged phospholipids of rHBsAg determine the interaction with these proteins. Although attachment of rHBsAg resembles the pro-inflammatory binding of LPS to CD14, rHBsAg does not activate monocytes and even reduces the expression of pro-inflammatory cytokines by LPS-stimulated monocytes. It is reported here that addition of rHBsAg to LPS-stimulated PBMC often results in increased secretion of IL-10, suggesting a similarity between the interaction of monocytes with apoptotic cells and rHBsAg. Using THP-1 cells, it is shown that IL-10 is not necessary to reduce TNFalpha protein levels. Addition of rHBsAg to LPS-stimulated cells reduces TNFalpha mRNA levels, but does not affect phosphorylation of p65 NF-kappaB and p38 MAP kinase. Instead, a reduced phosphorylation of ERK-1/2 and JNK-1/2 MAP kinases is observed.
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PMID:Recombinant HBsAg, an apoptotic-like lipoprotein, interferes with the LPS-induced activation of ERK-1/2 and JNK-1/2 in monocytes. 1227 Jan 19

This study was designed to systemically investigate the kinetics of extracellular signal-regulated kinase (ERK) 1/2, p54 c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) in lipopolysaccharide (LPS)-stimulated Kupffer cells (KC) simultaneously at the levels of protein expression, phosphorylation, and kinase activity, respectively, and their role in mediating pro- and anti-inflammatory cytokines. The protein expression, phosphorylation, and activities of these MAPKs in LPS-stimulated primary mouse KCs were determined with SDS-PAGE and western blotting using nonphosphorylated or phosphospecific antibodies or their corresponding substrates. The levels of TNF-alpha and IL-10 in culture supernatants were measured with ELISA kits. The results revealed that LPS stimulation, although not up- or downregulating the protein expression of ERK1/2, p54JNK, and p38 MAPKs in KCs, could induce rapid and significant activation of these kinases, with parallel profiles of changes in both phosphorylation and kinase activities. Although ERK1/2, p54JNK, and p38 kinases in LPS-stimulated KCs have similar kinetics of activation, the activation of ERK1/2 and p38 kinases was the most prominent. Inhibition of p38 MAPK with SB203580 inhibited the production of TNF-alpha and IL-10 by LPS-stimulated KCs, whereas blockade of ERK1/2 with PD98059 could reduce TNF-alpha production, but did not affect IL-10 production. Furthermore, PD98059 and SB203580 had an additive effect on TNF-alpha production, but PD98059 did not augment the SB203580-induced inhibition of IL-10 production. These data indicate that LPS stimulation, although not inducing any change in protein expression, results in rapid activation of ERK1/2, p54JNK, and p38 kinases in KCs, and that they may have different importance in the regulation of pro- and anti-inflammatory responses by LPS-stimulated KCs.
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PMID:Kinetics of mitogen-activated protein kinase family in lipopolysaccharide-stimulated mouse Kupffer cells and their role in cytokine production. 1239 77

Erythropoietin-producing hepatocyte (Eph) kinases represent the largest receptor tyrosine kinase family. Some of them are expressed in the T cell compartment, but their function in T cells is unknown. In peripheral blood, EphB6 was predominantly expressed on T cells, and was upregulated after culture. EphB6 crosslinking by anti-EphB6 mAb or ephrinB2 in the presence of suboptimal T cell receptor (TCR) stimulation led to drastic T cell proliferation, suggesting that EphB6 can co-stimulate T cells. The proliferation was accompanied by enhanced production of several lymphokines, such as IFN-gamma, IL-6, IL-10, TGF-beta, TNF-alpha, and GM-CSF, but not IL-2 and IL-4. Sorted EphB6(+) T cells had significantly stronger response to anti-CD3 and anti-CD28 stimulation than EphB6(-) T cells had. Taken together, these data suggest an important role of EphB6 in normal T cell activation. Within two minutes of anti-CD3 and anti-CD28 stimulation, EphB6 aggregated and colocalized with TCR, and this provides a morphological basis for EphB6 to enhance TCR signaling. The capping was followed by p38 MAPK activation, showing that EphB6 is capable of signaling, in spite of its lack of intrinsic kinase activity. This study demonstrates that interaction between EphB6 and its ligands facilitates T cell responses to antigen.
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PMID:EphB6 crosslinking results in costimulation of T cells. 1239 50

Alterations in the regulation of CD44 expression play a critical role in modulating cell adhesion, migration, and inflammation. LPS, a bacterial cell wall component, regulates CD44 expression and may modulate CD44-mediated biological effects in monocytic cells during inflammation and immune responses. In this study, we show that in normal human monocytes, LPS and LPS-induced cytokines IL-10 and TNF-alpha enhance CD44 expression. To delineate the mechanism underlying LPS-induced CD44 expression, we investigated the role of the mitogen-activated protein kinases (MAPKs), p38, p42/44 extracellular signal-regulated kinase, and c-Jun N-terminal kinase (JNK) by using their specific inhibitors. We demonstrate the involvement, at least in part, of p38 MAPK in TNF-alpha-induced CD44 expression in both monocytes and promonocytic THP-1 cells. However, neither p38 nor p42/44 MAPKs were involved in IL-10-induced CD44 expression in monocytes. To further dissect the TNF-alpha and LPS-induced signaling pathways regulating CD44 expression independent of IL-10-mediated effects, we used IL-10 refractory THP-1 cells as a model system. Herein, we show that CD44 expression induced by the LPS-mediated pathway predominantly involved JNK activation. This conclusion was based on results derived by transfection of THP-1 cells with a dominant-negative mutant of stress-activated protein/extracellular signal-regulated kinase kinase 1, and by exposure of cells to JNK inhibitors dexamethasone and SP600125. All these treatments prevented CD44 induction in LPS-stimulated, but not in TNF-alpha-stimulated, THP-1 cells. Furthermore, we show that CD44 induction may involve JNK-dependent early growth response gene activation in LPS-stimulated monocytic cells. Taken together, these results suggest a predominant role of JNK in LPS-induced CD44 expression in monocytic cells.
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PMID:Differential regulation of CD44 expression by lipopolysaccharide (LPS) and TNF-alpha in human monocytic cells: distinct involvement of c-Jun N-terminal kinase in LPS-induced CD44 expression. 1242 45


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