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)

Pyelonephritis, in which renal tubular epithelial cells are directly exposed to bacterial component, is a major predisposing cause of renal insufficiency. Although previous studies have suggested C-C chemokines are involved in the pathogenesis, the exact source and mechanisms of the chemokine secretion remain ambiguous. In this study, we evaluated the involvement of Toll-like receptors (TLRs) in C-C chemokine production by mouse primary renal tubular epithelial cells (MTECs). MTECs constitutively expressed mRNA for TLR1, 2, 3, 4, and 6, but not for TLR5 or 9. MTECs also expressed MD-2, CD14, myeloid differentiation factor 88, and Toll receptor-IL-1R domain-containing adapter protein/myeloid differentiation factor 88-adapter-like. Synthetic lipid A and lipoprotein induced monocyte chemoattractant protein 1 (MCP-1) and RANTES production in MTECs, which strictly depend on TLR4 and TLR2, respectively. In contrast, MTECs were refractory to CpG-oligodeoxynucleotide in chemokine production, consistently with the absence of TLR9. LPS-mediated MCP-1 and RANTES production in MTECs was abolished by NF-kappaB inhibition, but unaffected by extracellular signal-regulated kinase inhibition. In LPS-stimulated MTECs, inhibition of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase significantly decreased RANTES, but did not affect MCP-1 mRNA induction. Thus, MTECs have a distinct expression pattern of TLR and secrete C-C chemokines in response to direct stimulation with a set of bacterial components.
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PMID:Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells. 1216 29

The human lymphotoxin beta receptor (LTbetaR), a member of the tumor necrosis factor (TNF) receptor superfamily, is essential for not only the development and organization of secondary lymphoid tissues, but also for chemokine release. Even though LTbetaR was shown to recruit TNF-receptor-associated factor (TRAF) 2, 3, and 5, and to induce cell apoptosis or NF-kappaB activation, however, the downstream signaling leading to chemokine expression is not illustrated yet. In this study, we find that overexpression of LTbetaR in HEK293 cells increases IL-8 promoter activity and leads to IL-8 release. LTbetaR-induced IL-8 gene expression requires NF-kappaB (-80 to -71) and AP-1 (-126 to -12) binding sites located in IL-8 promoter, and NF-kappaB is more crucial than AP-1 for IL-8 gene expression. Reporter assay with dominant-negative mutants of TRAFs reveals that TRAF2, 3, and 5, as well as the downstream signal molecules NIK, IKKalpha, and IKKbeta, are involved in IL-8 gene expression. LTbetaR-mediated IL-8 response was inhibited by the dominant-negative mutants of ASK1, MKK4, MKK7, and JNK, but not by those of MEKK1, TAK1, MEK, ERK, and p38 MAPK. This suggests that IL-8 induction by LTbetaR is via TRAFs-elicited signaling pathways, including NIK/IKK-dependent NF-kappaB activation and ASK/MKK/JNK-dependent AP-1 activation.
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PMID:Lymphotoxin beta receptor induces interleukin 8 gene expression via NF-kappaB and AP-1 activation. 1216 72

Microglial cell phagocytic receptors may play important roles in the pathogenesis and treatment of several neurological diseases. We studied microglial Fc receptor (FcR) activation with respect to the specific FcgammaR types involved and the downstream signaling events by using monoclonal antibody (MAb)-coated Cryptococcus neoformans immune complexes as the stimuli and macrophage inflammatory protein 1alpha (MIP-1alpha) production as the final outcome. C. neoformans complexed with murine immunoglobulin G (IgG) of gamma1, gamma2a, and gamma3, but not gamma2b isotype, was effective in inducing MIP-1alpha in human microglia. Since murine gamma2b binds to human FcgammaRII (but not FcgammaRI or FcgammaRIII), these results indicate that FcgammaRI and/or FcgammaRIII is involved in MIP-1alpha production. Consistent with this, an antibody that blocks FcgammaRII (IV.3) failed to inhibit MIP-1alpha production, while an antibody that blocks FcgammaRIII (3G8) did. An anti-C. neoformans MAb, 18B7 (IgG1), but not its F(ab')(2), induced extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase kinase phosphorylation, and MIP-1alpha release was suppressed by the ERK inhibitor U0126. C. neoformans plus 18B7 also induced degradation of I-kappaBalpha, and MIP-1alpha release was suppressed by the antioxidant NF-kappaB inhibitor pyrrolidine dithiocarbamate. To confirm the role of FcR more directly, we isolated microglia from wild-type and various FcR-deficient mice and then challenged them with C. neoformans plus 18B7. While FcgammaRII-deficient microglia showed little difference from the wild-type microglia, both FcgammaRI alpha-chain- and FcgammaRIII alpha-chain-deficient microglia produced less MIP-1alpha, and the common Fc gamma-chain-deficient microglia showed no MIP-1alpha release. Taken together, our results demonstrate a definitive role for FcgammaRI and FcgammaRIII in microglial chemokine induction and implicate ERK and NF-kappaB as the signaling components leading to MIP-1alpha expression. Our results delineate a new mechanism for microglial activation and may have implications for central nervous system inflammatory diseases.
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PMID:Fcgamma receptor I- and III-mediated macrophage inflammatory protein 1alpha induction in primary human and murine microglia. 1218 68

We transduced dominant negative (dn) HIV TAT-Ras protein into mature human eosinophils to determine the signaling pathways and mechanism involved in integrin-mediated adhesion caused by cytokine, chemokine, and chemoattractant stimulation. Transduction of TAT-dnRas into nondividing eosinophils inhibited endogenous Ras activation and extracellular signal-regulated kinase (ERK) phosphorylation caused by IL-5, eotaxin-1, and fMLP. IL-5, eotaxin-1, or fMLP caused 1) change of Mac-1 to its active conformation and 2) focal clustering of Mac-1 on the eosinophil surface. TAT-dnRas or PD98059, a pharmacological mitogen-activated protein/ERK kinase inhibitor, blocked both focal surface clustering of Mac-1 and the change to active conformational structure of this integrin assessed by the mAb CBRM1/5, which binds the activation epitope. Eosinophil adhesion to the endothelial ligand ICAM-1 was correspondingly blocked by TAT-dnRas and PD98059. As a further control, we used PMA, which activates ERK phosphorylation by postmembrane receptor induction of protein kinase C, a mechanism which bypasses Ras. Neither TAT-dnRas nor PD98059 blocked eosinophil adhesion to ICAM-1, up-regulation of CBRM1/5, or focal surface clustering of Mac-1 caused by PMA. In contrast to beta(2)-integrin adhesion, neither TAT-dnRas nor PD98059 blocked the eosinophil adhesion to VCAM-1. Thus, a substantially different signaling mechanism was identified for beta(1)-integrin adhesion. We conclude that H-Ras-mediated activation of ERK is critical for beta(2)-integrin adhesion and that Ras-protein functions as the common regulator for cytokine-, chemokine-, and G-protein-coupled receptors in human eosinophils.
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PMID:Blockade of focal clustering and active conformation in beta 2-integrin-mediated adhesion of eosinophils to intercellular adhesion molecule-1 caused by transduction of HIV TAT-dominant negative Ras. 1219 40

Eotaxin is a critical chemokine eliciting migration of eosinophils and basophils in the pathogenesis of bronchial asthma. Recent studies have shown that the specific receptor for eotaxin, CCR3, is expressed in bronchial epithelial cells. Although mitogen-activated protein (MAP) kinases are involved in diverse cell functions of bronchial epithelial cells, their role in eotaxin signaling is unknown. In this study, we studied the activation and functional relevance of MAP kinases in bronchial epithelial cells stimulated with eotaxin. Eotaxin (1-100 nM) induced tyrosine/threonine phosphorylation and activation of extracellular regulated kinase (ERK) 1/2 and p38 in NCI-H(292) cells and normal human bronchial epithelial cells. The phosphorylation of these MAP kinases was detectable after 30 s, and peaked at 5 min. Eotaxin stimulated production of interleukin-8 and granulocyte macrophage colony-stimulating factor. Pretreatment of Compound X (a specific CCR3 antagonist), pertussis toxin, genistein, and wortmannin reduced the MAP kinase phosphorylation and cytokine production. The eotaxin-induced cytokine production was inhibited by specific inhibitors for MAP/ERK kinase (PD98059) and p38 MAP kinase (SB202190). These results suggest that both ERK1/2 and p38 MAP kinase activated by eotaxin have a critical role in the pathogenesis of asthma.
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PMID:The role of mitogen-activated protein kinases in eotaxin-induced cytokine production from bronchial epithelial cells. 1220 95

The acute respiratory distress syndrome (ARDS) is a major cause of morbidity after injury. We hypothesized that alveolar macrophage (AMPhi) chemokine and cytokine release after hemorrhage and sepsis is regulated by NF-kappaB and MAPK. Adult male rats underwent soft tissue trauma and hemorrhagic shock (~90 min) followed by crystalloid resuscitation. Sepsis was induced by cecal ligation and puncture (CLP) 20 h after resuscitation. AMPhi were harvested, and TNF-alpha, IL-6, and macrophage inflammatory protein (MIP)-2 release and serum IL-6 and TNF-alpha levels were measured at 5 h after HCLP. Lung tissues were analyzed for activation of NF-kappaB, myeloperoxidase activity, and wet/dry weight ratio. In control animals, AMPhi were stimulated with LPS with or without inhibitors of NF-kappaB and MAPK. Serum TNF-alpha and IL-6 levels and spontaneous AMPhi TNF-alpha and MIP-2 release were elevated (P < 0.05) after HCLP, concomitantly with the development of lung edema and leukocyte activation. Activation of NF-kappaB increased in lungs from the hemorrhage and CLP group compared with shams. Inhibition of NF-kappaB or the upstream MAPK significantly decreased LPS-stimulated AMPhi activation. Because enhanced release of inflammatory mediators by AMPhi may contribute to ARDS after severe trauma, inhibition of intracellular signaling pathways represents a target to attenuate organ injury under those conditions.
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PMID:Alveolar macrophage activation after trauma-hemorrhage and sepsis is dependent on NF-kappaB and MAPK/ERK mechanisms. 1222 57

Although the SDF-1 (CXCL12)/CXCR4 axis is important for B-cell development, it is not yet clear to what extent CC chemokines might influence B lymphopoiesis. In the current study, we characterized CC chemokine receptor 5 (CCR5) expression and function of primary progenitor B-cell populations in human bone marrow. CCR5 was expressed on all bone marrow B cells at levels between 150 and 200 molecules per cell. Stimulation of bone marrow B cells with the CCR5-binding chemokine macrophage inflammatory protein 1beta (MIP-1beta; CCL4) did not cause chemotaxis, but CCL4 was able to trigger potent calcium mobilization responses and activation of the mitogen-activated protein kinase (MAPK) pathway in developing B cells. We also determined that CCR5-binding chemokines MIP-1alpha (CCL3), CCL4, and RANTES (CCL5), specifically by signaling through CCR5, could affect all progenitor B-cell populations through a novel mechanism involving heterologous desensitization of CXCR4. This cross-desensitization of CXCR4 was manifested by the inhibition of CXCL12-induced calcium mobilization, MAPK activation, and chemotaxis. These findings indicate that CCR5 can indeed mediate biologic responses of bone marrow B cells, even though these cell populations express low levels of CCR5 on their cell surface. Thus, by modulation of CXCR4 function, signaling through CCR5 may influence B lymphopoiesis by affecting the migration and maturation of B-cell progenitors in the bone marrow microenvironment.
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PMID:CCR5-binding chemokines modulate CXCL12 (SDF-1)-induced responses of progenitor B cells in human bone marrow through heterologous desensitization of the CXCR4 chemokine receptor. 1223 39

We hypothesized that the CXC chemokine receptor-4 (CXCR4)-stromal-derived factor-1 (SDF-1) axis may be involved in metastasis of CXCR4(+) tumor cells into the bone marrow and lymph nodes, which secrete the alpha-chemokine SDF-1. To explore this hypothesis, we phenotyped by fluorescence-activated cell sorter analysis various human tumor cell lines for expression of CXCR4 and found that it was highly expressed on several rhabdomyosarcoma (RMS) cell lines. We also observed that cell lines derived from alveolar RMS, which is characterized by recurrent PAX3- and PAX7-FKHR gene fusions and is associated with a poor prognosis, expressed higher levels of CXCR4 than lines derived from embryonal RMS. Furthermore, transfer of a PAX3-FKHR gene into embryonal RMS cell activates CXCR4 expression. Because alveolar RMS frequently metastasizes to the bone marrow and lymph nodes, it seems that the CXCR4-SDF-1 axis could play an important role in this process. These findings prompted us to determine whether SDF-1 regulates the metastatic behavior of RMS cells. Accordingly, we found that, although SDF-1 did not affect proliferation or survival of these cell lines, it induced in several of them (1) phosphorylation of mitogen-activated protein kinase p42/44; (2) locomotion; (3) directional chemotaxis across membranes covered by laminin, fibronectin, or Matrigel; (4) adhesion to laminin, fibronectin, and endothelial cells; and (5) increased MMP-2 and diminished tissue inhibitors of metalloproteinases secretion. The small-molecule CXCR4-specific inhibitor, T140, effectively blocked the in vitro responses of RMS cells to SDF-1. On the basis of these observations we suggest that the CXCR4-SDF-1 axis may play an important role in tumor spread and metastasis of RMS cells to bone marrow and that molecular strategies aimed at inhibiting this axis could thus prove to be useful therapeutic measures.
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PMID:CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. 1223 74

beta-Amyloid accumulation is associated with pathologic changes in the brain in Alzheimer's disease and has recently been identified in plaques of another chronic inflammatory disorder, atherosclerosis. The class B scavenger receptor, CD36, mediates binding of fibrillar beta-amyloid to cells of the monocyte/macrophage lineage, including brain macrophages (microglia). In this study, we demonstrate that in microglia and other tissue macrophages, beta-amyloid initiates a CD36-dependent signaling cascade involving the Src kinase family members, Lyn and Fyn, and the mitogen-activated protein kinase, p44/42. Interruption of this signaling cascade, through targeted disruption of Src kinases downstream of CD36, inhibits macrophage inflammatory responses to beta-amyloid, including reactive oxygen and chemokine production, and results in decreased recruitment of microglia to sites of amyloid deposition in vivo. The finding that engagement of CD36 by beta-amyloid initiates a Src kinase-dependent production of inflammatory mediators in cells of the macrophage lineage reveals a novel receptor-mediated pro-inflammatory signaling pathway of potential therapeutic importance.
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PMID:A CD36-initiated signaling cascade mediates inflammatory effects of beta-amyloid. 1223 21

Interleukin 6 (IL-6) is known to play an important role in the biology of the malignant plasma cells in multiple myeloma. In an effort to better understand IL-6 stimulated myeloma cell growth, we have performed gene expression profiling to identify IL-6 early response genes. Using the KAS-6/1 IL-6-dependent human myeloma cell line, IL-6 stimulation dramatically induced expression of monocyte chemoattractant protein-1 (MCP-1) mRNA. To verify this result, we used reverse transcriptase PCR and RNAse protection assays and demonstrated using both assays that MCP-1 is indeed an IL-6 responsive gene in a variety of IL-6-responsive myeloma cell lines. Moreover, we also demonstrated IL-6 stimulated MCP-1 secretion by the myeloma cell lines as well as by fresh patient tumor cells. Lastly, we present evidence that fresh patient tumor cells express mRNA for the MCP-1 receptor, CCR2, as do myeloma cell lines along with a second MCP-1 receptor, CCR11. Although MM cell chemotaxis in response to MCP-1 was only minimal, we were able to demonstrate that MCP-1 stimulated activation of MAPK. Because of the important role that this chemokine plays in both angiogenesis and bone homeostasis, and the ability of MCP-1 to activate myeloma cells, these results suggest a new mechanism by which IL-6 may contribute to disease pathogenesis.
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PMID:Interleukin 6 induces monocyte chemoattractant protein-1 expression in myeloma cells. 1235 69


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