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)

Myeloid differentiation factor 88 (MyD88) is an essential intracellular signal transducer in Toll-like receptor (TLR) and interleukin (IL)-1 receptor family member-mediated cell activation. In order to characterize the role of MyD88 in pneumococcal meningitis we used gene-targeted mice lacking functional MyD88 expression. At 24 h after intracisternal infection, MyD88- deficient mice displayed a markedly diminished inflammatory host response in the CNS, as evidenced by reduced CSF pleocytosis and expression of cytokines, chemokines and complement factors. The reduced CNS inflammation was paralleled by a marked reduction in the prognostic relevant CNS complications, such as brain oedema formation. Nevertheless, MyD88 deficiency was associated with a worsening of disease which seemed to be attributable to severe bacteraemia. This notion was supported by the unexpected observation that infected MyD88-deficient mice displayed enhanced mRNA expression of inflammatory mediators [such as the proinflammatory cytokine tumour necrosis factor alpha (TNF-alpha) and the CXC chemokine macrophage inflammatory protein (MIP-2)] in the lung and consequently increased cell influx in the bronchoalveolar lavage fluid, compared with infected wild-type mice. Thus, the present study demonstrated for the first time an important role of MyD88 in immune activation to bacterial pathogens within the CNS. The role played by MyD88 in mounting an immune response to Streptococcus pneumoniae, however, seems to be dependent on the anatomical compartment involved.
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PMID:MyD88 is required for mounting a robust host immune response to Streptococcus pneumoniae in the CNS. 1511 15

Although being largely used for pathobiological models of cartilage diseases such as osteoarthritis (OA), human chondrocytes are still enigmatic cells, in as much as a large part of their secretome is unknown. We took advantage of the recent development of antibody-based microarrays to study multiple protein expression by human chondrocytes obtained from one healthy and five osteoarthritic joints, in unstimulated conditions or after stimulation by the proinflammatory cytokines interleukin-1 (IL-1) or tumour necrosis factor (TNF). The secretion media of chondrocytes were incubated with array membranes consisting of 79 antibodies directed against cytokines, chemokines, and angiogenic or growth factors. Several proteins were identified as new secretion products of chondrocytes, including the growth or angiogenic factors EGF, thrombopoietin, GDNF, NT-3 and -4, and PlGF, the chemokines ENA-78, MCP-2, IP-10, MIP-3alpha, NAP-2, PARC, and the cytokines MIF, IL-12, and IL-16. Most of the newly identified chemokines were increased intensely after stimulation by IL-1 or TNF, as for other proteins of the array, including GRO proteins, GM-CSF, IL-6, IL-8, MIP-1beta, GCP-2, and osteoprotegerin. The up-regulation by cytokines suggested that these proteins may participate in the destruction of cartilage and/or in the initiation of chemotactic events within the joint during OA. In conclusion, the microarray approach enabled to unveil part of an as yet unexplored chondrocyte secretome. Our findings demonstrated that chondrocytes were equipped with a proinflammatory arsenal of proteins which may play an important part in the pathogenesis of OA and/or its drift towards an inflammatory, rheumatoid phenotype.
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PMID:The inflammatory side of human chondrocytes unveiled by antibody microarrays. 1538 Oct 94

The expression of 10 genes implicated in regulation of the inflammatory processes in the lung was studied after exposure of alveolar macrophages (AMs) to silica in vitro or in vivo. Exposure of AMs to silica in vitro up-regulated the messenger RNA (mRNA) levels of three genes [interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2)] without a concomitant increase in the protein levels. AMs isolated after intratracheal instillation of silica up-regulated mRNA levels of four additional genes [granulocyte/macrophage-colony stimulating factor (GM-CSF), IL-1beta, IL-10, and inducible nitric oxide synthase]. IL-6, MCP-1, and MIP-2 protein levels were elevated in bronchoalveolar lavage fluid. Fibroblasts under basal culture conditions express much higher levels of IL-6 and GM-CSF compared with AMs. Coculture of AMs and alveolar type II cells, or coculture of AMs and lung fibroblasts, in contact cultures or Transwell chambers, revealed no synergistic effect. Therefore, such interaction does not explain the effects seen in vivo. Identification of the intercellular communication in vivo is still unresolved. However, fibroblasts appear to be an important source of inflammatory mediators in the lung.
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PMID:The sources of inflammatory mediators in the lung after silica exposure. 1557 13

Protein kinase C (PKC) isoforms are major regulators of cutaneous homeostasis and mediate inflammation in response to 12-O-tetradecanoylphorbol-13-acetate (TPA). We have previously reported that transgenic mice overexpressing PKCalpha in the skin exhibit severe intraepidermal neutrophilic inflammation and keratinocyte apoptosis when treated topically with TPA. Activation of PKCalpha increases the production of TNFalpha and the transcription of chemotactic factors (MIP-2, KC, S100A8/A9), vascular endothelial growth factor, and GM-CSF in K5-PKCalpha keratinocytes. In response to PKCalpha activation, NF-kappaB translocates to the nucleus and this is associated with IkappaB phosphorylation and degradation. Preventing IkappaB degradation reduces both the expression of inflammation-associated genes and chemoattractant release. To determine whether TNFalpha mediated NF-kappaB translocation and subsequent expression of proinflammatory factors, K5-PKCalpha mice were treated systemically with a dimeric soluble form of p75 TNFR (etanercept) or crossed with mice deficient for both TNFR isoforms, and keratinocytes were cultured in the presence of TNFalpha-neutralizing Abs. The in vivo treatment and TNFR deficiency did not prevent inflammation, and the in vitro treatment did not prevent NF-kappaB nuclear translocation after TPA. Together these results implicate PKCalpha as a regulator of a subset of cutaneous cytokines and chemokines responsible for intraepidermal inflammation independent of TNFalpha. PKCalpha inhibition may have therapeutic benefit in some human inflammatory skin disorders.
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PMID:Protein kinase C alpha-mediated chemotaxis of neutrophils requires NF-kappa B activity but is independent of TNF alpha signaling in mouse skin in vivo. 1566 32

We previously demonstrated that exposure to febrile-range hyperthermia (FRH) accelerates pathogen clearance and increases survival in murine experimental Klebsiella pneumoniae peritonitis. However, FRH accelerates lethal lung injury in a mouse model of pulmonary oxygen toxicity, suggesting that the lung may be particularly susceptible to injurious effects of FRH. In the present study, we tested the hypothesis that, in contrast with the salutary effect of FRH in Gram-negative peritonitis, FRH would be detrimental in multilobar Gram-negative pneumonia. Using a conscious, temperature-clamped mouse model and intratracheal inoculation with K. pneumoniae Caroli strain, we showed that FRH tended to reduce survival despite reducing the 3 day-postinoculation pulmonary pathogen burden by 400-fold. We showed that antibiotic treatment rescued the euthermic mice, but did not reduce lethality in the FRH mice. Using an intratracheal bacterial endotoxin LPS challenge model, we found that the reduced survival in FRH-treated mice was accompanied by increased pulmonary vascular endothelial injury, enhanced pulmonary accumulation of neutrophils, increased levels of IL-1beta, MIP-2/CXCL213, GM-CSF, and KC/CXCL1 in the bronchoalveolar lavage fluid, and bronchiolar epithelial necrosis. These results suggest that FRH enhances innate host defense against infection, in part, by augmenting polymorphonuclear cell delivery to the site of infection. The ultimate effect of FRH is determined by the balance between accelerated pathogen clearance and collateral tissue injury, which is determined, in part, by the site of infection.
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PMID:Febrile-range hyperthermia augments neutrophil accumulation and enhances lung injury in experimental gram-negative bacterial pneumonia. 1574 6

To study the effects of serum-free murine bone marrow endothelial cell conditioned medium (mBMEC-CM) on the growth of bone marrow endothelial cells, mBMEC-CM was collected and ultrafiltrated by Centriprep-10. The retentate of mBMEC-CM [molecular weight (MW)>10 kDa] and the filtrate of mBMEC-CM (MW<10 kDa) were obtained. The effect of bone marrow conditioned media, their components and exogenous cytokines on the formation of endothelial cell colonies were observed. The effect of bone marrow conditioned media, their components and exogenous cytokines on the proliferation of murine bone marrow endothelial cells were determined by [(3)H]-thymidine incorporation. The method of hybridizing to the Atlas cDNA array was used to determine the expression of cytokine mRNAs in bone marrow endothelial cells. The results obtained are as follows: vWF was expressed in bone marrow endothelial cells. The original mBMEC-CM and MW>10 kDa component of mBMEC-CM promoted the proliferation of bone marrow endothelial cell colonies and increased [(3)H]-thymidine incorporation of bone marrow endothelial cells. The MW<10 kDa component did not affect the production of endothelial cell colonies and did not increase [(3)H]-thymidine incorporation of endothelial cells. Six cytokines (IL-6, IL-11, SCF, GM-CSF, VEGF, bFGF) promoted the proliferation of bone marrow endothelial cell colonies. VEGF, bFGF and SCF increased [(3)H]-thymidine incorporation of bone marrow endothelial cells. According to the results of the Atlas cDNA array, GM-CSF,TGF-beta,BMP-2, bFGF, SCF, endothelin-2, thymosin beta10, MSP-1, connective tissue GF, PDGF-A chain, MIP-2 alpha, PlGF, neutrophil activating protein ENA-78, INF-gamma, IL-1, IL-6, IL-13, IL-11, inhibin-alpha mRNAs were expressed in endothelial cells. These results suggest that murine bone marrow endothelial cell conditioned medium promotes the proliferation of bone marrow endothelial cells.
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PMID:[Promoting effects of serum-free murine bone marrow endothelial cell conditioned medium on the growth of bone marrow endothelial cells]. 1583 Jan 5

Diesel exhaust particles (DEPs) at three concentrations (5, 35, and 50 mg/kg body weight) were instilled into rats intratracheally. We studied gene expression at 1, 7, and 30 days postexposure in cells obtained by bronchoalveolar lavage (BAL) and in lung tissue. Using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), we measured the mRNA levels of eight genes [interleukin (IL)-1beta, IL-6, IL-10, iNOS (inducible nitric oxide synthase), MCP-1 (monocyte chemoattractant protein-1), MIP-2 (macrophage inflammatory protein-2), TGF-beta1 (transforming growth factor-beta1), and TNF-alpha (tumor necrosis factor-alpha )] in BAL cells and four genes [IL-6, ICAM-1 (intercellular adhesion molecule-1), GM-CSF (granulocyte/macrophage-colony stimulating factor), and RANTES (regulated upon activation normal T cell expressed and secreted)] in lung tissue. In BAL cells on day 1, high-dose exposure induced a significant up-regulation of IL-1beta, iNOS, MCP-1, and MIP-2 but no change in IL-6, IL-10, TGF-beta1, and TNF-alpha mRNA levels. There was no change in the mRNA levels of IL-6, RANTES, ICAM-1, and GM-CSF in lung tissue. Nitric oxide production and levels of MCP-1 and MIP-2 were increased in the 24-hr culture media of alveolar macrophages (AMs) obtained on day 1. IL-6, MCP-1, and MIP-2 levels were also elevated in the BAL fluid. BAL fluid also showed increases in albumin and lactate dehydrogenase. The cellular content in BAL fluid increased at all doses and at all time periods, mainly due to an increase in polymorphonuclear leukocytes. In vitro studies in AMs and cultured lung fibroblasts showed that lung fibroblasts are a significant source of IL-6 and MCP-1 in the lung.
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PMID:Time course of gene expression of inflammatory mediators in rat lung after diesel exhaust particle exposure. 1586 72

Isocyanates are a common cause of occupational lung disease. Hexamethylene diisocyanate (HDI), a component of polyurethane spray paints, can induce respiratory symptoms, inflammation, lung function impairment, and isocyanate asthma. The predominant form of HDI in polyurethane paints is a nonvolatile polyisocyanate known as HDI biuret trimer (HDI-BT). Exposure of mice to aerosolized HDI-BT results in pathological effects, including pulmonary edema, lung inflammation, cellular proliferation, and fibrotic lesions, which occur with distinct time courses following exposure. To identify genes that mediate lung pathology in the distinct temporal phases after exposure, gene expression profiles in HDI-BT-exposed C57BL/6J mouse lungs were analyzed. RNase protection assay (RPA) of genes involved in apoptosis, cell survival, and inflammation revealed increased expression of IkappaBalpha, Fas, Bcl-X(L), TNFalpha, KC, MIP-2, IL-6, and GM-CSF following HDI-BT exposure. Microarray analysis of approximately 10000 genes was performed on lung RNA collected from mice 6, 18, and 90 h after HDI-BT exposure and from unexposed mice. Classes of genes whose expression was increased 6 h after exposure included those involved in stress responses (particularly oxidative stress and thiol redox balance), growth arrest, apoptosis, signal transduction, and inflammation. Types of genes whose expression was increased at 18 h included proteinases, anti-proteinases, cytoskeletal molecules, and inflammatory mediators. Transcripts increased at 90 h included extracellular matrix components, transcription factors, inflammatory mediators, and cell cycle regulators. This characterization of the gene expression profile in lungs exposed to HDI-BT will provide a basis for investigating injury and repair pathways that are operative during isocyanate-induced lung disease.
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PMID:Gene expression profiling in mouse lung following polymeric hexamethylene diisocyanate exposure. 1588 64

MyD88 is an adapter protein required for the induction of proinflammatory cytokines by most Toll-like receptors (TLR), and Pseudomonas aeruginosa expresses ligands for multiple TLRs. MyD88(-/-) (KO) mice are highly susceptible to aerosolized P. aeruginosa, failing to elicit an early inflammatory response and permitting a 3-log increase in bacterial CFU in the lungs by 24 h after infection. We hypothesized that alveolar macrophages are the first cells to recognize and kill aerosolized P. aeruginosa in an MyD88-dependent fashion due to their location within the airways. To determine which cells in the lungs mediate MyD88-dependent defenses against P. aeruginosa, we generated radiation bone marrow (BM) chimeras between MyD88KO and wild-type (WT) mice. MyD88KO mice transplanted with MyD88KO BM (MyD88KO-->MyD88KO mice) displayed uncontrolled bacterial replication, whereas all other chimeras controlled the infection by 24 h. However, at 4 h, both MyD88KO-->MyD88KO and WT-->MyD88KO mice permitted intrapulmonary bacterial replication, whereas MyD88KO-->WT and WT-->WT mice did not, indicating that the source of BM had little impact on the early control of infection. Similarly, the genotype of the recipient rather than that of the BM donor determined early neutrophil recruitment to the lungs. Whereas intrapulmonary TNF-alpha and IL-1beta production were associated with WT BM, levels of the CXC chemokines MIP-2 and KC as well as GM-CSF were associated with recipient genotype. We conclude that lung parenchymal and BM-derived cells collaborate in the MyD88-dependent response to P. aeruginosa infection in the lungs in mice.
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PMID:An essential role for non-bone marrow-derived cells in control of Pseudomonas aeruginosa pneumonia. 1610 80

Inflammatory mediators have been shown to play a major role in the complex series of co-ordinated events that occur in wound healing responses following injury. However, to date most of the studies carried out have addressed the expression, interactions and role of only one or two cytokines that are thought to be involved in wound repair. This study has evaluated, in murine skin samples taken at 0, 3, 12, 18, 24, 48, 72, 120 and 168 h post-wounding, the expression of a wide range of cytokines with potential for a role in wound repair. Various techniques (reverse transcription polymerase chain reaction (RT-PCR), bioassays and ELISA) were used to evaluate cytokine expression in these samples at both the mRNA and protein expressions level. Semi-quantitative analysis using RT-PCR revealed that IL-1beta, IP10, bFGF, and TGFbeta3 up-regulated in wounded samples, compared to non-injured control samples. Expression of mRNA for other cytokines and inflammatory mediators, IL-1alpha, IL-6, TGFbeta1, TNFalpha, MIP-1alpha, MIP-2, JE, KC, PDGFalpha and PDGFbeta, were found to be down-regulated in injured adult murine samples compared to normal control samples. Interestingly we failed to find evidence of mRNA expression for the cytokines IL-2, IL-4, IL-12, GM-CSF, IFNgamma and RANTES, in both non-injured and injured samples. These observations were also generally supported by the results obtained using bioassays for IL-1 and IL-6 and ELISA for IL-1alpha, IL-1beta, IL-6, TNFalpha, and IFNgamma.
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PMID:Cytokine gene expression in a murine wound healing model. 1610 71


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