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)

A crucial event for the induction of an anti-viral immune response is the coordinated, phenotype-dependent migration of dendritic cells (DC) to sites of infection and secondary lymphoid organs. Here we show that the vaccinia virus (VV) strains Western Reserve (WR) and modified virus Ankara (MVA) inhibit directional migration of mature DC toward the lymphoid chemokines CCL19 and CXCL12 without affecting surface expression of the respective chemokine receptors or impairing undirected cellular locomotion. Instead, infection with VV results in a deficiency of extracellular signal-regulated kinase-1 and a disturbance of intracellular calcium mobilization, indicating a viral interference with signaling events downstream of the surface chemokine receptors. In immature DC, apart from inhibiting chemokine-induced migration of infected DC, infection with both VV strains increases expression of the inflammatory chemokine receptors CCR1 and CXCR1 on non-infected bystander DC, which depends on the activity of IFN-alpha. Although functional, these chemokine receptors are resistant to lipopolysaccharide-induced down-regulation. In addition, VV-infected and non-infected bystander DC fail to up-regulate the lymphoid chemokine receptor CCR7 upon activation, together pointing to a disability to undergo the chemokine receptor switch. This study shows that VV targets directional migration of professional antigen-presenting cells at multiple functional levels, revealing a potent viral strategy of immune escape.
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PMID:Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells. 1735 4

Dendritic cell (DC) activation is a critical event for the induction of an immune response to haptens. Although signaling pathways such as mitogen-activated protein kinase (MAPK) family members have been reported to play a role in DC activation by haptens, little is known about the implication of the nuclear factor kappa B (NF-kappaB) pathway. In this work, we showed that NiSO(4) induced the expression of HLA-DR, CD83, CD86, and CD40 and the production of interleukin (IL)-8, IL-6, and IL-12p40 in human DCs, whereas DNCB induced mainly the expression of CD83 and CD86 and the production of IL-8. NiSO(4) but not DNCB was able to activate the degradation of IkappaB-alpha leading to the binding of the p65 subunit of NF-kappaB on specific DNA probes. Inhibition of the NF-kappaB pathway using BAY 11-7085 prevents both CD40 and HLA-DR expression and cytokine production induced by NiSO(4). However, BAY 11-7085 only partially inhibited CD86 and CD83 expression induced by NiSO(4). In addition, p38 MAPK and NF-kappaB were independently activated by NiSO(4) since SB203580 did not inhibit NF-kappaB activation by NiSO(4). Interestingly, we also showed that DNCB inhibited the degradation of IkappaB-alpha induced by tumor necrosis factor-alpha leading to alteration of CD40, HLA-DR, and CD83 expression but not of CD86 and CCR7. Extensive modifications of DC phenotype by NiSO(4) in comparison to DNCB are probably the consequence of NF-kappaB activation by NiSO(4) but not by DNCB.
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PMID:NF-kappaB plays a major role in the maturation of human dendritic cells induced by NiSO(4) but not by DNCB. 1763 46

Although the development of an acidic tissue environment or acidosis is a hallmark of inflammatory processes, few studies analyze the effect of extracellular pH on immune cells. We have previously shown that exposure of murine dendritic cells (DCs) to pH 6.5 stimulates macropinocytosis and cross-presentation of extracellular Ags by MHC class I molecules. We report that the transient exposure of human DCs to pH 6.5 markedly increases the expression of HLA-DR, CD40, CD80, CD86, CD83, and CCR7 and improves the T cell priming ability of DCs. Incubation of DCs at pH 6.5 results in the activation of the PI3K/Akt and the MAPK pathways. Using specific inhibitors, we show that the maturation of DCs induced by acidosis was strictly dependent on the activation of p38 MAPK. DC exposure to pH 6.5 also induces a dramatic increase in their production of IL-12, stimulating the synthesis of IFN-gamma, but not IL-4, by Ag-specific CD4(+) T cells. Interestingly, we find that suboptimal doses of LPS abrogated the ability of pH 6.5 to induce DC maturation, suggesting a cross-talk between the activation pathways triggered by LPS and extracellular protons in DCs. We conclude that extracellular acidosis in peripheral tissues may contribute to the initiation of adaptive immune responses by DCs, favoring the development of Th1 immunity.
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PMID:Extracellular acidosis triggers the maturation of human dendritic cells and the production of IL-12. 1764 Oct 62

Angiogenesis is an essential component of chronic inflammation that is linked to carcinogenesis. In this study, we report that human vascular endothelial growth inhibitor (VEGI, TNF superfamily 15), an endothelial cell-produced antiangiogenic cytokine, induces mouse dendritic cell (DC) maturation, a critical event in inflammation-initiated immunity. VEGI-stimulated bone marrow-derived immature DCs display early activation of maturation signaling molecules NF-kappaB, STAT3, p38, and JNK, and cytoskeleton reorganization and dendrite formation. The activation signals are partially inhibited by using a neutralizing Ab against death domain-containing receptor-3 (DR3) or a truncated form of DR3 consisting of the extracellular domain, indicating an involvement of DR3 in the transmission of VEGI activity. A VEGI isoform, TL1A, does not induce similar activities under otherwise identical experimental conditions. Additionally, the cells reveal significantly enhanced expression of mature DC-specific marker CD83, secondary lymphoid tissue-directing chemokine receptor CCR7, the MHC class-II protein (MHC-II), and costimulatory molecules CD40, CD80, and CD86. Functionally, the cells exhibit decreased Ag endocytosis, increased cell surface distribution of MHC-II, and increased secretion of IL-12 and TNF. Moreover, VEGI-stimulated DCs are able to facilitate the differentiation of CD4+ naive T cells in cocultures. These findings suggest that the anticancer activity of VEGI arises from coupling the inhibition of endothelial cell growth with the promotion of the adaptive immune mechanisms through the stimulation of DC maturation.
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PMID:The endothelial cell-produced antiangiogenic cytokine vascular endothelial growth inhibitor induces dendritic cell maturation. 1778 11

B-cell chronic lymphocytic leukemia (B-CLL) progression is frequently accompanied by clinical lymphadenopathy, and the CCL21 chemokine may play an important role in this process. Indeed, CCR7 (the CCL21 receptor), as well as matrix metalloproteinase-9 (MMP-9), are overexpressed in infiltrating B-CLL cells. We have studied whether MMP-9 is regulated by CCL21 and participates in CCL21-dependent migration. CCL21 significantly increased B-CLL MMP-9 production, measured by gelatin zymography. This was inhibited by blocking extracellular signal-regulated kinase-1/2 (ERK1/2) activity or by cell transfection with CCR7-siRNA. Accordingly, CCL21/CCR7 interaction activated the ERK1/2/c-Fos pathway and increased MMP-9 mRNA. CCL21-driven B-CLL cell migration through Matrigel or human umbilical vein endothelial cells (HUVEC) was blocked by anti-CCR7 antibodies, CCR7-siRNA transfection, or the ERK1/2 inhibitor U0126, as well as by anti-MMP-9 antibodies or tissue inhibitor of metalloproteinase 1 (TIMP-1). These results strongly suggest that MMP-9 is involved in B-CLL nodal infiltration and expand the roles of MMP-9 and CCR7 in B-CLL progression. Both molecules could thus constitute therapeutic targets for this disease.
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PMID:Matrix metalloproteinase-9 is up-regulated by CCL21/CCR7 interaction via extracellular signal-regulated kinase-1/2 signaling and is involved in CCL21-driven B-cell chronic lymphocytic leukemia cell invasion and migration. 1789 Apr 52

Nerve growth factor (NGF) has been shown to play important roles in the differentiation, function, and survival of immune cells, contributing to immune responses and pathogenesis of autoimmune diseases. Dendritic cells (DCs) are a potent initiator for immune and inflammatory responses upon recognition of pathogens via Toll-like receptors (TLR). However, expression of NGF and its receptors on human monocyte-derived DCs (MoDCs) and the role of NGF in the response of DCs to TLR ligands remain to be investigated. In the present study, we demonstrate that there were weak expressions of NGF and no expression of NGF receptors p140(TrkA) and p75(NTR) on human immature MoDCs, however, the expression of NGF and p75(NTR) on MoDCs could be significantly up-regulated by LPS in a dose- and time-dependent manner. NGF could markedly promote LPS-induced expression of HLA-DR, CD40, CD80, CD83, CD86, CCR7, secretion of IL-12p40 and proinflammatory cytokines IL-1, IL-6, TNF-alpha, and the T cell-stimulating capacity of MoDCs, indicating that NGF can promote LPS-induced DC maturation. The promoting effect of NGF on LPS-induced MoDCs maturation could be completely abolished by pretreatment of MoDCs with p75(NTR) antagonist, suggesting that LPS-induced p75(NTR) mediates the effect. Furthermore, increased activation of the p38MAPK and NF-kappaB pathways has been shown to be responsible for the NGF-promoted DC maturation. Therefore, NGF facilitates TLR4 signaling-induced maturation of human DCs through LPS-up-regulated p75(NTR) via activation of p38 MAPK and NF-kappaB pathways, providing another mechanism for the involvement of NGF in the immune responses and pathogenesis of autoimmune diseases.
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PMID:Nerve growth factor promotes TLR4 signaling-induced maturation of human dendritic cells in vitro through inducible p75NTR 1. 1794 6

Lactoferrin (LF) is an important protein component of the innate immune system that is broadly distributed within the body fluids. LF is endowed with multiple biological activities. Talactoferrin (TLF), a recombinant human LF, is in clinical development as an anticancer agent and is entering Phase III clinical trials. Here, we show that TLF induces the maturation of human dendritic cells (DCs) derived from monocytes. TLF, at physiologically relevant concentrations (100 microg/ml) up-regulates the expression of human leukocyte antigen (HLA) class II, CD83, CD80, and CD86 costimulatory molecule and CXCR4 and CCR7 chemokine receptors, acting primarily through the p38 MAPK signaling pathway. DCs matured by TLF displayed an enhanced release of IL-8 and CXCL10, as well as a significantly reduced production of IL-6, IL-10, and CCL20. They also display a reduced ability to take up antigen and increased capacity to trigger proliferation and release IFN-gamma in the presence of allogeneic human T cells. TLF-matured DCs are able to prime naive T cells to respond to KLH antigen and display a significantly increased capacity to present Flu-MA(58-66) peptide to HLA-A2-matched T cells. These data suggest that a key immunomodulatory function that may be mediated by TLF is to link the innate with adaptive immunity through DC maturation.
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PMID:Lactoferrin, a major defense protein of innate immunity, is a novel maturation factor for human dendritic cells. 1836 98

Chemokines are known to regulate the chemotaxis of leukocytes and play an important role in immunological processes. Chemokine receptors are widely distributed in hematopoietic cells and are often co-localized with the hematopoietic-specific G(16) and its close relative, G(14). Yet, many chemokine receptors utilize pertussis toxin-sensitive G(i) proteins for signaling. Given that both G(16) and G(14) are capable of linking G(i)-coupled receptors to the stimulation of phospholipase Cbeta, we examined the capacity of six CC chemokine receptors (CCR1, CCR2a, CCR2b, CCR3, CCR5 and CCR7) to interact with G(14) and G(16) in a heterologous expression system. Among the CC chemokine receptors tested, CCR1, CCR2b, and CCR3 were capable of mediating chemokine-induced stimulation of phospholipase Cbeta via either G(14) or G(16). The G(14)/G(16)-mediated responses exhibited CC chemokine dose-dependency and were resistant to pertussis toxin (PTX) treatment. In contrast, CCR2a, CCR5 and CCR7 were unable to interact with G(14) and G(16). Under identical experimental conditions, all six CC chemokine receptors were fully capable of inhibiting adenylyl cyclase via G(i) as well as stimulating phospholipase Cbeta via 16z44, a G(16/z) chimera that possesses increased promiscuity toward G(i)-coupled receptors. Moreover, CCR1-mediated ERK1/2 phosphorylation was largely PTX-insensitive in THP-1 monocytic cells that endogenously express Galpha(16). In addition, CCR1 agonist was less efficacious in mediating chemotaxis of THP-1 cells following the knockdown of Galpha(16) by overexpressing siRNA, indicating the participation of Galpha(16) in CCR1-induced cell migration. These results show that different CC chemokine receptors can discriminate against G(14) and G(16) for signal transduction.
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PMID:Differential involvement of Galpha16 in CC chemokine-induced stimulation of phospholipase Cbeta, ERK, and chemotaxis. 1840 77

Dendritic cells (DC) and complement are both important effectors in innate immunity, and also potent linkers between innate immunity and adaptive immunity. As key components of innate immunity, various bioactive complement components produced at the inflammatory sites have been found to be able to regulate functions of DC. It is well known that migration of DC to the peripheral inflammatory sites benefits the recognition and uptake of invading pathogens by DC as antigen-presenting cells, and DC migration to secondary lymphatic tissues benefits the priming and activation of T cells. However, up to date, little is known about the underlying signaling mechanisms for the regulation of DC migration by the multifunctional molecule C1q, the first member of classical pathway. In this study, we show that C1q mediates the chemotaxis and transendothelial migration of immature MoDC. Additionally, C1q significantly enhances the chemotaxis of LPS-induced mature DC to CCL19 via upregulation of CCR7 expression. Activation of PI3K/AKT, ERK and JNK pathways is required for the chemotaxis of immature DC to C1q, meanwhile activation of AKT and P38 pathways is required for the C1q-mediated enhancement of mature DC chemotaxis to CCL19. Therefore, our results suggest that C1q, actively produced and accumulated at the inflammatory sites, can directly chemoattract immature DC from blood to peripheral inflammatory tissues, and promotes the migration of mature DC to secondary lymph organs via activation of AKT and MAPK pathways, thus outlining new way for favoring the link of innate immunity to adaptive immunity.
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PMID:Complement C1q chemoattracts human dendritic cells and enhances migration of mature dendritic cells to CCL19 via activation of AKT and MAPK pathways. 1883 69

Toll-like receptors (TLRs) act to sense the environment for microbial products and submit danger signals to antigen-presenting cells (APCs) resulting in activation of complex immune responses. In this study, we analyzed the function of human monocyte-derived APCs generated in vitro in the presence of interleukin (IL)-10 upon activation by TLR ligands. Exposure of these APCs to IL-10 resulted in a skewed phenotypic maturation in response to stimuli provided by the TLR ligands, a reduced cytokine production, such as IL-12, IL-6 or tumor necrosis factor-alpha, and impaired capacity to stimulate T-cell activation. Furthermore, CCR7 upregulation in APCs exposed to TLR stimulation as well as migration towards CCL19/MIP-3beta were strongly reduced. IL-10 was found to downregulate MyD88, IRAK1 (IL-1 receptor-associated kinase) and tumor necrosis factor receptor-associated factor 6, essential adaptor molecules for TLR signaling, and to decrease TLR-induced nuclear expression of the nuclear factor-kappaB transcription factors c-Rel and Rel-B as well as interferon regulatory factor (IRF)-3 and IRF-8. This was not due to the inhibition of the mitogen-activated protein kinase pathway, but was rather mediated by the blockage of the PI3K signaling cascade. Interestingly, the inhibition of proteins involved in TLR signaling, such as MyD88, IRAK1 and mammalian target of rapamycin, was due to a selective post-transcriptional regulation.
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PMID:Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells. 1900 81


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