Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.59 (MIP)
 4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of rat peritoneal neutrophils with staurosporine (64 nM) induced production of macrophage inflammatory protein-2 (MIP-2) and phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase/MAP kinase (ERK/MAPK). The staurosporine-induced MIP-2 production at 4 h was inhibited by the highly specific p38 MAPK inhibitor SB 203580 and the MAPK/ERK kinase (MEK-1) inhibitor PD 98059 in a concentration-dependent manner. By treatment with SB 203580 (1 microM) or PD 98059 (50 microM), the staurosporine-induced increase in the levels of mRNA for MIP-2 was only partially lowered, although the staurosporine-induced MIP-2 production was completely inhibited. Consistent with the inhibition by the protein synthesis inhibitor cycloheximide, SB 203580 and PD 98059 inhibited MIP-2 production at 4 h either when added simultaneously with staurosporine or 2 h after stimulation with staurosporine. In contrast, the DNA-dependent RNA polymerase inhibitor actinomycin D did not inhibit MIP-2 production at 4 h when it was added 2 h after staurosporine stimulation. Dot blot analysis demonstrated that treatment with SB 203580 or PD 98059 down-regulates the stability of MIP-2 mRNA. These results suggested that p38 MAPK and ERK/MAPK pathways are involved in translation of MIP-2 mRNA to protein and stabilization of MIP-2 mRNA.
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PMID:Involvement of p38 MAPK and ERK/MAPK pathways in staurosporine-induced production of macrophage inflammatory protein-2 in rat peritoneal neutrophils. 1035 7

Early inflammatory events include cytokine release, activation, and rapid accumulation of neutrophils, with subsequent recruitment of mononuclear cells. The p38 mitogen-activated protein kinase (MAPK) intracellular signaling pathway plays a central role in regulating a wide range of inflammatory responses in many different cells. A murine model of mild LPS-induced lung inflammation was developed to investigate the role of the p38 MAPK pathway in the initiation of pulmonary inflammation. A novel p38 MAPK inhibitor, M39, was used to determine the functional consequences of p38 MAPK activation. In vitro exposure to M39 inhibited p38 MAPK activity in LPS-stimulated murine and human neutrophils and macrophages, blocked TNF-alpha and macrophage inflammatory protein-2 (MIP-2) release, and eliminated migration of murine neutrophils toward the chemokines MIP-2 and KC. In contrast, alveolar macrophages required a 1000-fold greater concentration of M39 to block release of TNF-alpha and MIP-2. Systemic inhibition of p38 MAPK resulted in significant decreases in the release of TNF-alpha and neutrophil accumulation in the airspaces following intratracheal administration of LPS. Recovery of MIP-2 and KC from the airspaces was not affected by inhibition of p38 MAPK, and accumulation of mononuclear cells was not significantly reduced. When KC was instilled as a proinflammatory stimulus, neutrophil accumulation was significantly decreased by p38 MAPK inhibition independent of TNF-alpha or LPS. Together, these results demonstrate a much greater dependence on the p38 MAPK cascade in the neutrophil when compared with other leukocytes, and suggest a means of selectively studying and potentially modulating early inflammation in the lung.
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PMID:Role of p38 mitogen-activated protein kinase in a murine model of pulmonary inflammation. 1065 69

The mechanisms involved in anti-inflammatory action of transforming growth factor beta (TGFbeta) have been examined by evaluating its effect on chemokine gene expression in mouse macrophages. Lipopolysaccharide (LPS)-stimulated expression of the CXC chemokines KC and MIP-2 was selectively reduced by TGFbeta in a time- and protein synthesis-dependent process. While TGFbeta had a modest effect on transcription of the KC and MIP-2 mRNAs as measured by nuclear run-on, it had no effect on LPS-stimulated luciferase expression driven by the KC promoter nor on the activation of nuclear factor kappaB (NFkappaB) DNA-binding activity and transactivation function. Interestingly, KC mRNA levels were markedly reduced by TGFbeta treatment in cells transfected with KC genomic or cDNA constructs driven from either the KC or cytomegalovirus (CMV) promoters, demonstrating the importance of sequences within the mature mRNA and suggesting that suppression may involve a posttranscriptional mechanism. In support of this possibility, LPS stimulation prolonged the half-life of KC mRNA and this stabilization response was blocked in cells treated with TGFbeta. Examination of KC mRNA expressed under control of a tetracycline-responsive promoter demonstrated that TGFbeta prevented stabilization of KC mRNA, in response to LPS but did not alter KC mRNA half-life directly. KC mRNA stabilization by LPS was dependent on activation of p38 mitogen-activated protein kinase (MAPK) activity, and TGFbeta treatment inhibited p38 MAPK activation. These findings support the hypothesis that TGFbeta-mediated suppression of chemokine gene expression involves antagonism of LPS-stimulated KC mRNA stabilization via inhibition of p38 MAPK.
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PMID:TGFbeta inhibits LPS-induced chemokine mRNA stabilization. 1271 27

In Alzheimer's disease (AD) one finds increased deposition of A beta and also an increased presence of monocytes/macrophages in the vessel wall and activated microglial cells in the brain. AD patients show increased levels of proinflammatory cytokines by activated microglia. Here we used a human monocytic THP-1 cell line as a model for microglia to delineate the cellular signaling mechanism involved in amyloid peptides (A beta(1-40) and A beta(1-42))-induced expression of inflammatory cytokines and chemokines. We observed that A beta peptides at physiological concentrations (125 nM) increased mRNA expression of cytokines (TNF-alpha, and IL-1 beta) and chemokines (monocyte chemoattractant protein-1 (MCP-1), IL-8, and macrophage inflammatory protein-1 beta (MIP-1 beta)). The cellular signaling involved activation of c-Raf, extracellular signal-regulated kinase-1 (ERK-1)/ERK-2, and c-Jun N-terminal kinase, but not p38 mitogen-activated protein kinase. This is further supported by the data showing that A beta causes phosphorylation of ERK-1/ERK-2, which, in turn, activates Elk-1. Furthermore, A beta mediated a time-dependent increase in DNA binding activity of early growth response-1 (Egr-1) and AP-1, but not of NF-kappa B and CREB. Moreover, A beta-induced Egr-1 DNA binding activity was reduced >60% in THP-1 cells transfected with small interfering RNA duplexes for Egr-1 mRNA. We show that A beta-induced expression of TNF-alpha, IL-1 beta, MCP-1, IL-8, and MIP-1 beta was abrogated in Egr-1 small inhibitory RNA-transfected cells. Our results indicate that A beta-induced expression of cytokines (TNF-alpha and IL-1 beta) and chemokines (MCP-1, IL-8, and MIP-1 beta) in THP-1 monocytes involves activation of ERK-1/ERK-2 and downstream activation of Egr-1. The inhibition of Egr-1 by Egr-1 small inhibitory RNA may represent a potential therapeutic target to ameliorate the inflammation and progression of AD.
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PMID:Amyloid peptide-induced cytokine and chemokine expression in THP-1 monocytes is blocked by small inhibitory RNA duplexes for early growth response-1 messenger RNA. 1273 78

Using rat peritoneal neutrophils, the complete nucleotide sequence of rat macrophage inflammatory protein-2 (MIP-2) mRNA including 5'untranslated region (UTR) and 3'UTR was determined (GenBank Accession number, AB060092). It was found that the MIP-2 mRNA has a 70 bp 5'UTR, a 303 bp coding region and a 728 bp 3'UTR which contains adenylate/uridylate (AU)-rich areas defined as AU-rich elements (AREs). Site-directed mutagenesis studies using the tetracycline-sensitive transactivator protein-expressing rat basophilic leukemia cells (RBL-2H3-TO cells) revealed that MIP-2 mRNA mutants which lack the 3'UTR are more stable than MIP-2-wild-type (wt) mRNA. A MIP-2 mRNA mutant in which some mutations were introduced to the ARE was also stable. The stability of MIP-2 mRNA was low in untreated RBL-2H3-TO cells, but it increased in the antigen-stimulated immunoglobulin E (IgE)-sensitized cells. The antigen-induced MIP-2 mRNA stabilization was counteracted by the highly specific p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 and the MAPK/ERK kinase (MEK-1) inhibitor PD98059. These findings indicate that ARE is the cis-element which mediates the rapid decay of MIP-2 mRNA, and the antigen stimulation stabilizes MIP-2 mRNA and the p38 MAPK and p44/42 MAPK pathways are involved in the antigen-induced stabilization of MIP-2 mRNA.
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PMID:Analysis of the mechanism regulating the stability of rat macrophage inflammatory protein-2 mRNA in RBL-2H3 cells. 1462 57

We describe the gene structure, regulation, signal transduction. and functions of a cytokine, interleukin (IL)-32. An IL-18 unresponsive cell was converted to a responsive cell by transfection of the IL-18 receptor beta chain, and IL-18-induced microarray revealed high expression of a cytokine-like gene. Although IL-32 does not share sequence homology with known cytokine families, IL-32 induces various cytokines, human TNFalpha, and IL-8 in THP-1 monocytic cells as well as mouse TNFalpha and MIP-2 in Raw macrophage cells. IL-32 activates typical cytokine signal pathways of nuclear factor-kappa B (NF-kappaB) and p38 mitogen-activated protein kinase. IL-32 mRNA is highly expressed in immune tissue rather than other tissues. Human IL-32 exists as four splice variants, and IL-32 from other species were found as expressed sequence tag clones in the databank. Induced in human peripheral lymphocyte cells after mitogen stimulation, in human epithelial cells by IFNgamma, and in NK cells after exposure to the combination of IL-12 plus IL-18, IL-32 may play a role in inflammatory/autoimmune diseases.
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PMID:Interleukin-32: a cytokine and inducer of TNFalpha. 1566 65

An increase in circulating neutrophils is a characteristic feature of many inflammatory reactions and is a result of the rapid mobilization of neutrophils from the bone marrow, driven by inflammatory mediators, including the ELR + CXC chemokines. In this paper, using a combination of light and electron microscopy and an in situ perfusion system of the rat femoral bone marrow, we examined this mobilization process in detail. We show that mobilization of neutrophils stimulated by the CXC chemokine, rat MIP-2, involves neutrophil migration from the haematopoietic compartment of the bone marrow across the bone marrow sinusoidal endothelium via a transcellular route. The critical role of the bone marrow sinusoidal endothelium in regulating neutrophil mobilization was demonstrated by artificially disrupting the bone marrow endothelial barrier by treatment with cytochalasin D, which results in the non-selective release of leucocytes from the bone marrow. In contrast, inhibiting the activity of p38 mitogen-activated protein kinase, inhibited both MIP-2 stimulated chemotaxis of bone marrow neutrophils in vitro and neutrophil mobilization in situ while, a broad spectrum matrix metalloproteinase inhibitor, BB94, had no effect on neutrophil mobilization. These results support the hypothesis that neutrophil migration drives their mobilization and highlights the function of the sinusoidal endothelium in regulating this process.
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PMID:Migration across the sinusoidal endothelium regulates neutrophil mobilization in response to ELR + CXC chemokines. 1847 53

Heat shock protein (HSP) 72 is released by cells during stress and injury. HSP-72 also stimulates the release of cytokines in macrophages by binding to Toll-like receptors (TLR) 2 and 4. Circulating levels of HSP-72 increase during hepatic ischemia-reperfusion injury. The role of extracellular HSP-72 (eHSP-72) in the injury response to ischemia-reperfusion is unknown. Therefore, the objective of the present study was to determine whether eHSP-72 has any direct effects on hepatocytes. Primary mouse hepatocytes were treated with purified human recombinant HSP-72. Conditioned media were evaluated by ELISA for the cytokines, TNF-alpha, IL-6, and macrophage inflammatory protein 2 (MIP-2). Stimulation of hepatocytes with eHSP-72 did not induce production of TNFalpha or IL-6 but resulted in dose-dependent increases in MIP-2 production. To evaluate the pathway responsible for this response, expression of TLR2 and TLR4 was confirmed on hepatocytes by immunohistochemistry. Hepatocyte production of MIP-2 was significantly decreased in hepatocytes obtained from TLR2 or TLR4 knockout mice. MIP-2 production was found to be partially dependent on NF-kappaB because inhibition of NF-kappaB with Bay 11-7085 significantly decreased eHSP-72-induced MIP-2 production. Inhibitors of p38 mitogen-activated protein kinase or c-Jun NH(2)-terminal kinase had no effect on production of MIP-2 induced by eHSP-72. The data suggest that eHSP-72 binds to TLR2 and TLR4 on hepatocytes and signals through NF-kappaB to increase MIP-2 production. The fact that eHSP-72 did not increase TNF-alpha or IL-6 production may be indicative of a highly regulated signaling pathway downstream from TLR.
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PMID:Activation of hepatocytes by extracellular heat shock protein 72. 1850 12

Neuroprogenitor cells are an important resource because of their great potential to replace damaged cells in the brain caused by trauma and disease. Studies have shown that when neuroprogenitor cells are transplanted into the brain they migrate towards damaged areas, suggesting that these areas express factors that recruit migrating cells. Generally, after neuronal injury, there is a neuroinflammatory response that results in increased chemokine production. In this present study, we demonstrate that monocyte chemoattractant protein-1 (MCP-1) significantly induces the migration of NT2 neuroprogenitor cells. Activation of intracellular cyclic adenosine monophosphate or protein kinase C with forskolin and phorbol 12-myristate 13-acetate, respectively, was able to completely abolish the MCP-1-induced migration. Contrarily, neither extracellular signal-regulated kinase nor p38 mitogen-activated protein kinase was required for NT2 cells to respond to MCP-1. Previously, we showed that amyloid precursor protein (APP) activity increases MCP-1 expression in NT2 cells. We now demonstrate that NT2 cells expressing APP can induce migration of other neuroprogenitor cells. Utilizing a MCP-1 neutralizing antibody, we discovered that APP-induced migration was not caused solely by increased MCP-1 production. Interestingly, APP-increased expression of several C-C chemokines: MCP-1, regulated upon activation, normal T-cell expressed, and secreted (RANTES), and macrophage inflammatory protein alpha (MIP-1 alpha). This demonstrates the unique role APP has in regulating chemokine production, which directly affects cell migration. Taken together, these data provides greater detail of the chemotactic factors and intracellular signaling that direct neuroprogenitor cell migration, allowing for better understanding of cell migration during transplantation.
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PMID:MCP-1-induced migration of NT2 neuroprogenitor cells involving APP signaling. 1904 68

Production of chemokines in dendritic cells (DCs) may be crucial in modulating immune responses generated through Toll-like receptor (TLR)-mediated recognition of microbial products. We evaluated chemokine production in DCs induced by TLR agonists and investigated the role of signaling pathways. DCs were generated from mouse bone marrow cells cultured with Fms-like tyrosine kinase-3 ligand and stimulated with a wide array of individual TLR agonists or simultaneously with pairs of combinations. Production of monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1 (MIP-1/CCL3) and regulated on activation, normal T cell expressed and secreted (RANTES/CCL5), were determined in cell culture supernatants by ELISA or cytokine cytometric bead array. Pharmacological inhibitors of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), nuclear factor-kappaB (NF-kB) and phosphatidylinositol 3-kinase (PI3K), were used to investigate the role of signaling pathways. TLR agonists induced significantly elevated MCP-1, RANTES, and MIP-1. Production of RANTES and MIP-1 was particularly prominent after stimulation of DCs with TLR3 (Poly(I:C)), and TLR7/8 (R848) or TLR9 (CpG ODN) agonists, respectively. However, down-modulation of chemokine production was observed in simultaneously TLR-stimulated DCs. A positive role was identified for NF-kB, PI3K and ERK, whereas JNK had a negative regulatory effect on chemokine production in DCs. Positive and negative regulatory roles for the p38 MAPK pathway were observed. Thus, chemokine levels differed and most notably there was down-modulation of chemokines in DCs stimulated with combined TLR agonists. Furthermore, analysis of signaling pathways revealed a role for MAPKs in positive and negative regulation of chemokine production in DCs. The chemokine response of DCs induced by TLR agonists appears complex and could have important implications for vaccine design.
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PMID:Regulation of Toll-like receptor-induced chemokine production in murine dendritic cells by mitogen-activated protein kinases. 2045 Dec 53


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