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)

Expression of the chitinase 3-like protein HC-gp39 (human cartilage glycoprotein 39) is associated with conditions of increased matrix turnover and tissue remodelling. High levels of this protein have been found in sera and synovial fluids of patients with inflammatory and degenerative arthritis. In order to assess the role of HC-gp39 in matrix degradation induced by inflammatory cytokines, we have examined its effect on the responses of connective tissue cells to TNF-alpha (tumour necrosis factor-alpha) and IL-1 (interleukin-1) with respect to activation of signalling pathways and production of MMPs (matrix metalloproteases) and chemokines. Stimulation of human skin fibroblasts or articular chondrocytes with IL-1 or TNF-alpha in the presence of HC-gp39 resulted in a marked reduction of both p38 mitogen-activated protein kinase and stress-activated protein kinase/Jun N-terminal kinase phosphorylation, whereas nuclear translocation of nuclear factor kappaB proceeded unimpeded. HC-gp39 suppressed the cytokine-induced secretion of MMP1, MMP3 and MMP13, as well as secretion of the chemokine IL-8. The suppressive effects of HC-gp39 were dependent on phosphoinositide 3-kinase activity, and treatment of cells with HC-gp39 resulted in AKT-mediated serine/threonine phosphorylation of apoptosis signal-regulating kinase 1. This process could therefore be responsible for the down-regulation of cytokine signalling by HC-gp39. These results suggest a physiological role for HC-gp39 in limiting the catabolic effects of inflammatory cytokines.
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PMID:The chitinase 3-like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha. 1501 34

Mature dendritic cells (DCs) are central to the development of optimal T cell immune responses. CD40 ligand (CD40L, CD154) is one of the most potent maturation stimuli for immature DCs. We studied the role of three signaling pathways, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and phosphoinositide-3-OH kinase (PI3K), in CD40L-induced monocyte-derived DC activation, survival, and expansion of virus-specific CD8(+) T cell responses. p38 MAPK pathway was critical for CD40L-mediated up-regulation of CD83, a marker of DC maturation. CD40L-induced monocyte-derived DC IL-12 production was mediated by both the p38 MAPK and PI3K pathways. CD40L-mediated DC survival was mostly mediated by the PI3K pathway, with smaller contributions by p38 MAPK and ERK pathways. Finally, the p38 MAPK pathway was most important in mediating CD40L-stimulated DCs to induce strong allogeneic responses as well as expanding virus-specific memory CD8(+) T cell responses. Thus, although the p38 MAPK, PI3K, and ERK pathways independently affect various parameters of DC maturation induced by CD40L, the p38 MAPK pathway within CD40L-conditioned DCs is the most important pathway to maximally elicit T cell immune responses. This pathway should be exploited in vivo to either completely suppress or enhance CD8(+) T cell immune responses.
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PMID:The role of the p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and phosphoinositide-3-OH kinase signal transduction pathways in CD40 ligand-induced dendritic cell activation and expansion of virus-specific CD8+ T cell memory responses. 1512 88

High mobility group box protein 1 (HMGB1), a DNA binding nuclear and cytosolic protein, is a proinflammatory cytokine released by monocytes and macrophages. This study addressed the hypothesis that HMGB1 is an immunostimulatory signal that induces dendritic cell (DC) maturation. We show that HMGB1, via its B box domain, induced phenotypic maturation of DCs, as evidenced by increased CD83, CD54, CD80, CD40, CD58, and MHC class II expression and decreased CD206 expression. The B box caused increased secretion of the proinflammatory cytokines IL-12, IL-6, IL-1alpha, IL-8, TNF-alpha, and RANTES. B box up-regulated CD83 expression as well as IL-6 secretion via a p38 MAPK-dependent pathway. In the MLR, B box-activated DCs acted as potent stimulators of allogeneic T cells, and the magnitude of the response was equivalent to DCs activated by exposure to LPS, nonmethylated CpG oligonucleotides, or CD40L. Furthermore, B box induced secretion of IL-12 from DCs as well as IL-2 and IFN-gamma secretion from allogeneic T cells, suggesting a Th1 bias. HMGB1 released by necrotic cells may be a signal of tissue or cellular injury that, when sensed by DCs, induces and/or enhances an immune reaction.
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PMID:High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization. 1521 Jul 88

In the present work, we provide data supporting that CD70, a tumor necrosis factor (TNF)-related molecule, defined as the CD27 ligand (CD27L), may actively regulate T cell functions similarly to other members of the TNF family (i.e., CD40L and CD30L). Cross-linking CD70 with specific monoclonal antibodies (mAb) stimulated cytotoxicity and cytokine production in human T cell clones. Detection of intracellular-free calcium mobilization and mitogen-activated protein kinase phosphorylation upon mAb engagement of CD70 further supported an active signaling role for the TNF-related molecule. Similar results were obtained in the Jurkat leukaemia T cell line stably transfected with CD70; in that system, induction of Akt phosphorylation was detected, indirectly revealing the involvement of the phosphatidylinositol-3 kinase pathway. Stimulation of CD70+ Jurkat cells, with a CD70-specific mAb or with COS-7 cells transiently transfected with CD27, induced transcriptional activity detectable by different reporter gene expression systems. Altogether, our data point out that a reciprocal communication may be established between CD27+ and CD70+ cells during the immune response.
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PMID:Signalling via CD70, a member of the TNF family, regulates T cell functions. 1522 68

In this study, we describe the expression and function of CD40, a TNF receptor family member, in cervical carcinomas. CD40 was present at very low levels in normal cervical epithelium but was overexpressed in human papillomavirus-infected lesions and advanced squamous carcinomas of the cervix. The stimulation of CD40-positive cervical carcinoma cell lines with soluble CD40L (CD154) resulted in activation of the NF-kappaB and MAPK signaling pathways and up-regulation of cell surface markers and intracellular molecules associated with Ag processing and presentation. Concomitantly, the CD154-induced activation of CD40 in carcinoma cells was found to directly influence susceptibility to CTL-mediated killing. Thus, CD40 stimulation in cervical carcinoma cell lines expressing a TAP-dependent human papillomavirus 16 E6 Ag epitope resulted in their enhanced killing by specific CTLs. However, CD154 treatment of carcinoma cells expressing proteasome-dependent but TAP-independent Ags from the EBV-encoded BRLF1 and BMLF1 failed to increase tumor cell lysis by specific CTLs. Moreover, we demonstrate that chemotherapeutic agents that suppress protein synthesis and reverse the CD40-mediated dissociation of the translational repressor eukaryotic initiation factor 4E-binding protein from the initiation factor eukaryotic initiation factor 4E, such as 5-fluorouracil, etoposide, and quercetin, dramatically increase the susceptibility of cervical carcinoma cells to CD40L-induced apoptosis. Taken together, these observations demonstrate the functional expression of CD40 in epithelial tumors of the cervix and support the clinical exploitation of the CD40 pathway for the treatment of cervical cancer through its multiple effects on tumor cell growth, apoptosis, and immune recognition.
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PMID:Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis. 1561 Dec 26

The interaction between CD40 and its ligand, CD154, has been shown to play a role in the onset and maintenance of inflammatory disease. Contributing to this process is the ability of CD40 to signal monocyte and macrophage inflammatory cytokine production. We have shown that this event is dependent on Src family tyrosine kinase activity and the subsequent activation of ERK1/2. To address the role of TNFR-associated factor (TRAF) family members in facilitating this signaling pathway, we transfected a CD40-deficient macrophage cell line with wild-type human CD40, or with CD40 containing disrupted TRAF binding sites. Ligation of either wild-type CD40, or a CD40 mutant unable to bind TRAF2/3/5, resulted in the stimulation of inflammatory cytokine production. However, ligation of a CD40 mutant lacking a functional TRAF6 binding site did not initiate inflammatory cytokine production, and this mutant was found to be defective in CD40-mediated activation of ERK1/2, as well as IkappaB kinase (IKK) and NF-kappaB. Likewise, introduction of a dominant-negative TRAF6 into a wild-type (CD40(+)) macrophage cell line resulted in abrogation of CD40-mediated induction of inflammatory cytokine synthesis. Finally, treatment of monocytes with a cell-permeable peptide corresponding to the TRAF6-binding motif of CD40 inhibited CD40 activation of ERK1/2, IKK, and inflammatory cytokine production. These data demonstrate that TRAF6 acts as a critical adapter of both the Src/ERK1/2 and IKK/NF-kappaB proinflammatory signaling pathways in monocytes and macrophages.
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PMID:TNF receptor-associated factor 6 is an essential mediator of CD40-activated proinflammatory pathways in monocytes and macrophages. 1563 33

The role of CD40/CD154 ligation in the upregulation of genes of the proinflammatory nuclear factor-kappaB (NF-kappaB) signal transduction pathway was explored in primary cultures of human renal proximal tubule epithelial cells. Using a cDNA gene array specific for human NF-kappaB signal pathway genes, 38 genes were upregulated at 1 h, and 7 of these genes remained upregulated at 3 h. Of these genes, intercellular adhesion molecule-1 (ICAM-1) was explored in further detail. Quantitative real-time PCR for ICAM-1 mRNA expression confirmed the gene array findings. Western blot analysis and quantitative sandwich-enzyme ELISA confirmed this observation at the protein level. A cell-surface ELISA assay showed that ICAM-1 expression doubled by 48 h of CD154 exposure, and fluorescence-activated cell sorter analysis suggested that both the number of cells expressing ICAM-1 and the expression of ICAM-1 on these cells had increased. A cell adhesion assay using fluorescein-labeled human peripheral mononuclear cells showed that ICAM-1 upregulation resulted in increased mononuclear cell adhesion to the monolayer, which was abrogated by pretreatment of the monolayer with a neutralizing ICAM-1 antibody. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB-203580 but not the extracellular signal-regulated kinase 1/2 inhibitor (PD-98059) nor the protein kinase C inhibitor (calphostin) blunted ICAM-1 expression and mononuclear cell adhesion to the monolayer. We conclude that, in human renal proximal tubule epithelial cells, CD40 activation upregulates ICAM-1 (and other NF-kappaB pathway genes) expression with concomitant enhanced adhesion of mononuclear cells, which is mediated via the p38 MAPK signal transduction pathway.
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PMID:CD40/CD154 ligation induces mononuclear cell adhesion to human renal proximal tubule cells via increased ICAM-1 expression. 1571 10

Bystander B cells may be initially stimulated through CD40, which enhances susceptibility to Fas-mediated apoptosis, before encountering Ag, which produces Fas resistance. A key issue in this process is to what extent CD40 cross-talk might affect subsequent BCR signaling. It has previously been shown that CD40 engagement bypasses or mitigates the need for Bruton's tyrosine kinase in subsequent BCR signaling for NF-kappaB activation. However, the full extent of the effects of CD40 on BCR signaling has not been delineated. In the present study we evaluated the possibility that CD40-mediated cross-talk also affects another principal outcome of BCR signaling: MAPK activation. We found that prior stimulation of primary murine B cells with CD40L markedly enhanced the level of ERK and JNK (but not p38 MAPK) phosphorylation produced by subsequently added anti-Ig Ab, and much, but not all, of this enhancement was independent of PI3K and phospholipase C. CD40L treatment similarly enhanced BCR-induced MAPK kinase (MEK) phosphorylation, and MEK was required for enhancement of ERK. Although BCR-induced c-Raf phosphorylation was also enhanced by prior CD40L treatment, c-Raf was not required for MEK/ERK phosphorylation. These results identify a novel system of receptor cross-talk between CD40 and BCR and indicate that the effects of CD40 engagement on subsequent BCR stimulation spread beyond NF-kappaB to involve the MAPK pathway.
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PMID:B cell receptor (BCR) cross-talk: CD40 engagement enhances BCR-induced ERK activation. 1574 69

Tubular epithelial cells (TEC) play an important role in tubulointerstitial inflammation, a hallmark of most renal diseases, via production of cytokines and chemokines. In this study, the role of mitogen-activated protein kinases (MAPK) in regulation of the proinflammatory cytokine IL-6 in cultured human TEC in response to the leukocyte-derived factors IL-1, TNF-alpha, IL-17, and CD40L was investigated. IL-6 production induced by IL-1, TNF-alpha, and IL-17 was specifically inhibited by the c-jun NH(2)-terminal kinase (JNK) inhibitor SP600125, but not by a selective inhibitor of p38 MAPK, and was moderately increased when the ERK1/2 pathway was inhibited. Also for CD40L stimulation, inhibition of JNK resulted in a pronounced inhibition of IL-6 production. Although stimulation of TEC induced activation of activator protein-1 (AP-1), the down-stream target of JNK, reporter assays demonstrated that mutation of the AP-1 binding site in the IL-6 promoter did not affect gene transcription. Furthermore, IL-1-induced transcriptional activation of the IL-6 promotor was repressed by SP600125 or by co-transfection of a dominant-negative expression plasmid of c-jun even in the absence of a functional AP-1 binding site. This suggests that IL-6 production by renal epithelial cells is regulated by JNK, via a mechanism, however, independent of the AP-1 binding site. The data rather suggest that the JNK pathway may interfere with other signaling pathways, involving NF-kappaB and possibly ERK.
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PMID:NF-kappaB mediated IL-6 production by renal epithelial cells is regulated by c-jun NH2-terminal kinase. 1584 70

Monoclonal antibodies (mAb) directed against lineage-specific B-cell antigens have provided clinical benefit for patients with hematologic malignancies, but to date no antibody-mediated immunotherapy is available for multiple myeloma. In the present study, we assessed the efficacy of a fully human anti-CD40 mAb CHIR-12.12 against human multiple myeloma cells. CHIR-12.12, generated in XenoMouse mice, binds to CD138-expressing multiple myeloma lines and freshly purified CD138-expressing cells from >80% multiple myeloma patients, as assessed by flow cytometry. Importantly, CHIR-12.12 abrogates CD40L-induced growth and survival of CD40-expressing patient multiple myeloma cells in the presence or absence of bone marrow stromal cells (BMSC), without altering constitutive multiple myeloma cell proliferation. Immunoblotting analysis specifically showed that PI3-K/AKT, nuclear factor-kappaB (NF-kappaB), and extracellular signal-regulated kinase activation induced by CD40L (5 mug/mL) was inhibited by CHIR-12.12 (5 mug/mL). Because CD40 activation induces multiple myeloma cell adhesion to both fibronectin and BMSCs, we next determined whether CHIR-12.12 inhibits this process. CHIR-12.12 decreased CD40L-induced multiple myeloma cell adhesion to fibronectin and BMSCs, whereas control human IgG1 did not. Adhesion of multiple myeloma cells to BMSCs induces interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion, and treatment of multiple myeloma cells with CD40L further enhanced adhesion-induced cytokine secretion; conversely, CHIR-12.12 blocks CD40L-enhanced IL-6 and VEGF secretion in cocultures of multiple myeloma cells with BMSCs. Finally, CHIR-12.12 triggered lysis of multiple myeloma cells via antibody-dependent cellular cytotoxicity (ADCC) but did not induce ADCC against CD40-negative multiple myeloma cells, confirming specificity against CD40-expressing multiple myeloma cells. These results provide the preclinical rationale for clinical trials of CHIR-12.12 to improve patient outcome in multiple myeloma.
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PMID:Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. 1599 68


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