Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study examined the contribution of monocyte chemotactic protein-1 (MCP-1) to granulomatous inflammation mediated by Th1- and Th2-related cytokines. Types 1 and 2 lung granulomas (GR) were respectively induced in presensitized CBA mice by embolization of beads coupled to purified protein derivative of Mycobacteria tuberculosis or soluble Ags derived from Schistosoma mansoni eggs. MCP-1 was spontaneously produced by intact GR, isolated GR macrophages, and draining lymph node cultures, but levels were greater in the type 2 than in the type 1 response. In vivo depletion of IFN-gamma augmented type 2 inflammation and local MCP production; IL-4 depletion had the opposite effect. These treatments had no significant effect on the type 1 response. Treatment with anti-MCP-1, but not that with anti-MIP-1alpha, Abs caused a 30% decrease in type 2 GR area. Neither treatment affected the type 1 GR. Intrinsic MCP-1 was detected immunohistochemically within lymph nodes and appeared to support IL-4-/IL-5-producing lymph node cells. In addition, MCP-1 inhibited IL-12 production by inflammatory macrophages. The latter was demonstrated as a potentially direct effect of MCP-1 on macrophages. These findings show that MCP-1 contributes more to type 2 than to type 1 cytokine-mediated inflammation and suggest a broader role for chemokines in regulating Th cell expression.
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PMID:Role of monocyte chemoattractant protein-1 (MCP-1) in Th1 (mycobacterial) and Th2 (schistosomal) antigen-induced granuloma formation: relationship to local inflammation, Th cell expression, and IL-12 production. 890 39

The effects of a Ca2(+)-ATPase inhibitor, cyclopiazonic acid (CPA), and two hydroquinone-antioxidants, 2,5-di-(tert-butyl)-1,4-hydroquinone (DTBHQ) and 2,5-di-(tert-amyl)-1,4-hydroquinone (DTAHQ) on the release of IL-4 and MCP-1 from RBL-2H3 cells were investigated. CPA, DTBHQ and DTAHQ, all of which induce intracellular free Ca2+ concentration ([Ca2+]i) increase, induced IL-4 and MCP-1 release in a dose-dependent manner. The release of TNF-alpha required both a Ca2(+)-ATPase inhibitor and 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the Ca2(+)-ATPase inhibitors induced IL-4 and MCP-1 production without TPA. The release of IL-4 and MCP-1 reached a maximum at 9 and 6 h, respectively. IL-4 and MCP-I release was inhibited by treatment with the immunosuppressant FK-506 and actinomycin D. Therefore, in our system IL-4 and MCP-1 release involves Ca2(+)-dependent and FK-506-sensitive signaling pathways. This is the first report about Th-2 type cytokine and chemokine production in RBL-2H3 cells.
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PMID:Ca2+-ATPase inhibitor induces IL-4 and MCP-1 production in RBL-2H3 cells. 986 97

In-situ hybridization with labeled oligonucleotide probes was applied to explore cytokine and chemokine mRNA expression in sections of striated muscle, the target organ in experimental autoimmune myasthenia gravis (EAMG), induced in Lewis rats by immunization with acetylcholine receptor (AChR) and complete Freund's adjuvant (CFA). A transient burst of TNF-alpha, IL-1beta and IL-6 mRNA expressing cells was detected during the early phase of EAMG. This cytokine pattern was related to muscular infiltration of macrophages. Levels of IL-4, IL-10, IFN-gamma, cytolysin and TGF-beta mRNA expressing cells were low and observed mainly during the early phase of EAMG. C-C chemokine RANTES, MCP, MIP-1alpha and MIP-2 mRNA expressing cells were not detected over the course of EAMG. The low and transient expression of cytokines in EAMG muscle tissues suggests that the immune effector responses are unlikely operated by infiltrating cells in muscle. Muscular infiltrations in EAMG are unlikely due to local accumulation of C-C chemokines.
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PMID:Cytokine and chemokine mRNA expressing cells in muscle tissues of experimental autoimmune myasthenia gravis. 987 80

The proopiomelanocortin (POMC)-derived neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) is known to modulate some aspects of inflammation through direct effects on T cells, B cells, and monocytes. To determine whether alpha-MSH might similarly influence mast cell responsiveness, mast cells were examined to see if they expressed the receptor for alpha-MSH, melanocortin-1 (MC-1), and whether alpha-MSH altered mast cell function. We thus first identified MC-1 on bone marrow cultured murine mast cells (BMCMC) and a murine mast cell line (MCP-5) employing flow cytometry and through detection of specific binding. Subsequent treatment of mast cells with alpha-MSH increased the cAMP concentration in a characteristic biphasic pattern, demonstrating that alpha-MSH could affect intracellular processes. We next examined the effect of alpha-MSH on mediator release and cytokine expression. IgE/DNP-human serum albumin-stimulated histamine release from mast cells was inhibited by approximately 60% in the presence of alpha-MSH. Although activation of BMCMC induced the expression of mRNAs for the inflammatory cytokines IL-1beta, IL-4, IL-6, TNF-alpha, and the chemokine lymphotactin, mRNAs for IL-1beta, TNF-alpha, and lymphotactin were down-modulated in the presence of alpha-MSH. Finally, IL-3-dependent proliferative activity of BMCMC was slightly but significantly augmented by alpha-MSH. Taken together, these observations suggest that alpha-MSH may exert an inhibitory effect on the mast cell-dependent component of a specific inflammatory response.
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PMID:Receptor-mediated modulation of murine mast cell function by alpha-melanocyte stimulating hormone. 1047 6

Inflammatory stimuli and lipid peroxidation activate nuclear factor kappa B (NF-kappaB) and upregulate proinflammatory cytokines and chemokines. The present study evaluated the relationship between pathological liver injury, endotoxemia, lipid peroxidation, and NF-kappaB activation and imbalance between pro- and anti-inflammatory cytokines. Rats (5 per group) were fed ethanol and a diet containing saturated fat, palm oil, corn oil, or fish oil by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. Pathological analysis was performed and measurements of endotoxin were taken, lipid peroxidation, NF-kappaB, and messenger RNA (mRNA) levels of proinflammatory cytokines (tumor necrosis factor-alpha [TNFalpha], interleukin-1 beta [IL-1beta], interferon-gamma, [IFN-gamma], and IL-12), C-C chemokines (regulated upon activation, normal T cell expressed and secreted [RANTES], monocyte chemotactic protein [MCP]-1, macrophage inflammatory protein [MIP]-1alpha), C-X-C chemokines (cytokine induced neutrophil chemoattractant (CINC), MIP-2, IP-10, and epithelial neutrophil activating protein [ENA]-78), and anti-inflammatory cytokines (IL-10, IL-4, and IL-13). Activation of NF-kappaB and increased expression of proinflammatory cytokines C-C and C-X-C chemokines was seen in the rats exhibiting necroinflammatory injury (fish oil-ethanol [FE] and corn oil-ethanol[CE]). These groups also had the highest levels of endotoxin and lipid peroxidation. Levels of IL-10 and IL-4 mRNA were lower in the group exhibiting inflammatory liver injury. Thus, activation of NF-kappaB occurs in the presence of proinflammatory stimuli and results in increased expression of proinflammatory cytokines and chemokines. The Kupffer cell is probably the major cell type showing activation of NF-kappaB although the contribution of endothelial cells and hepatocytes cannot be excluded. Downregulation of anti-inflammatory cytokines may additionally exacerbate liver injury.
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PMID:Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat. 1049 45

The contribution of IL-4 and IL-13 to inflammation and cytokine responses was compared in mice with types-1 or -2 pulmonary granulomas (GR) elicited by beads bound to antigens of Mycobacteria bovis (PPD) or Schistosoma mansoni eggs (SEA). Type-2 SEA-GR produced the most IL-4 and IL-13. Type-1 PPD-GR produced detectable IL-13, but not IL-4. Mice were treated with anti-IL4 or anti-IL-13 Abs, then lesion size/composition, cytokine/chemokine mRNA and lymph node cytokines were measured. Type-1 GRs resisted individual Abs, but combined Abs augmented lesions by 20%. In contrast, anti-IL-4 abrogated type-2 GR by 30-40% and eosinophil recruitment by 60%. Anti-IL-13 abrogated type-2 GR by 20-30% with no effect on eosinophils. Combined depletion reduced lesion area by 60% and eosinophils by more than 80%. In type-1 GR lungs, anti-IL-4 and anti-IL-13 augmented IFNgamma and TNFalpha mRNA. In type 2 lungs, anti-IL-13 did likewise, but anti-IL-4 decreased TNFalpha without affecting IFNgamma mRNA. In both responses, IL-4 promoted MCP-1 and MCP-5 mRNA, but IL-13 inhibited chemokines in type-1 GR. In lymph nodes, anti-IL-4, but not anti-IL-13, abrogated type-2 cytokines. In fact, IL-13 down-regulated itself and other type-2 cytokines. In summary, IL-4 and IL-13 have common and disparate regulatory functions in types 1 and 2 responses.
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PMID:Interleukin 4 and 13 participation in mycobacterial (type-1) and schistosomal (type-2) antigen-elicited pulmonary granuloma formation: multiparameter analysis of cellular recruitment, chemokine expression and cytokine networks. 1085 56

Asperigillus fumigatus spores or conidia are quickly eliminated from the airways of nonsensitized individuals but persist in individuals with allergic pulmonary responsiveness to fungus. A. fumigatus-induced allergic airway disease is characterized by persistent airway hyperreactivity, inflammation, and fibrosis. The present study explored the role of CCR2 ligands in the murine airway response to A. fumigatus conidia. Nonsensitized and A. fumigatus-sensitized CBA/J mice received an intratracheal challenge of A. fumigatus conidia, and pulmonary changes were analyzed at various times after conidia. Whole lung levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), but neither MCP-3/CCL7 nor MCP-5/CCL12, were significantly elevated at days 3 and 7 after conidia in nonsensitized mice. MCP-1/CCL2 was significantly increased in lung samples from A. fumigatus-sensitized mice at days 14 and 30 after a conidia challenge. Administration of anti-MCP-1/CCL2 antiserum to nonsensitized mice for14 days after the conidia challenge attenuated the clearance of conidia and significantly increased airway hyperreactivity, eosinophilia, and peribronchial fibrosis compared with nonsensitized mice that received conidia and normal serum. Adenovirus-directed overexpression of MCP-1/CCL2 in A. fumigatus-sensitized mice markedly reduced the number of conidia, airway inflammation, and airway hyperresponsiveness at day 7 after the conidia challenge in these mice. Immunoneutralization of MCP-1/CCL2 levels in A. fumigatus-sensitized mice during days14-30 after the conidia challenge did not affect the conidia burden but significantly reduced airway hyperreactivity, lung IL-4 levels, and lymphocyte recruitment into the airways compared with the control group. These data suggest that MCP-1/CCL2 participates in the pulmonary antifungal and allergic responses to A. fumigatus conidia.
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PMID:Antifungal and airway remodeling roles for murine monocyte chemoattractant protein-1/CCL2 during pulmonary exposure to Asperigillus fumigatus conidia. 1116 Feb 30

Dendritic cells (DC) are professional antigen-presenting cells (APC) which proceed from immature to a mature stage during their final differentiation. Immature DC are highly effective in terms of antigen uptake and processing, whereas mature DC become potent immunostimulatory cells. Until now, the expression profiles of the major components of the MHC class I antigen-processing machinery (APM) during DC development have not been well characterized. In this study, the mRNA and protein expression levels of the IFN-gamma inducible proteasome subunits, of the proteasome activators PA28, and of key components required for peptide transport and MHC class I-peptide complex assembly have been evaluated in immature and mature stages of human monocyte-derived DC using semiquantitative RT-PCR and Western blot analyses. The IFN-gamma-responsive immunoproteasome subunits LMP2, LMP7 and MECL1 are up-regulated in immature DC, whereas the other components of the MHC class I presentation machinery, such as PA28, TAP, tapasin, and HLA heavy and light chains, were found to be more abundant in mature DC. These findings support the hypothesis that immature DC produced by the differentiation of monocytes in response to IL-4 and granulocyte macrophage colony stimulating factor first increase their capacity to capture antigens and process them into peptides, thereby switching from housekeeping to immunoproteasomes, while mature DC rather up-regulate the components required for peptide translocation and MHC class I-peptide complex formation, and thus specialize in antigen presentation. Our results establish that MHC class I, like MHC class II surface expression, is markedly regulated during DC development and maturation.
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PMID:Bipartite regulation of different components of the MHC class I antigen-processing machinery during dendritic cell maturation. 1171 92

Cytokine and chemokine responses during anamnestic type-1 and type-2 lung granuloma formation were evaluated in mice at 6,12,18 and 24-months of age. Lesions were induced by embolizing Sepharose beads coupled to Mycobacterium bovis purified protein derivative or soluble Schistosoma mansoni egg antigens. Type-1 inflammation was reduced by 18 months, whereas type-2 granulomas not until 24 months of age. In type-1 draining lymph nodes cultures, interferon-gamma (IFNgamma) declined to a nadir by 18, and then partly recovered at 24 months. In contrast, IL-4 was not significantly impaired in type-2 cultures until 24 months. Type-1 and 2 node cultures also displayed decreased IL-13, but paradoxically enhanced IL-5 production at 24 months. Chemokine transcripts in granulomatous lungs displayed age-related alterations. In the type-1 response, CXCL9 (monokine-induced by IFNgamma) declined with age then partly recovered at 24 months parallelling lymph node IFNgamma levels. Transcripts for MIP-2/CXCL2, IP-10/CXCL10, MCP-1/CCL2, and MCP-5/CCL12 increased at 24 months. In the type-2 response MCP-1/CCL2, MCP-3/CCL7, MCP-5/CCL12 and TARC/CCL17 collapsed at 24 months paralleling local IL-4 transcript levels, yet some chemokine transcripts such as KC/CXCL1 and eotaxin/CCL11 were unaffected. These findings suggest that cytokine and chemokine responses degrade differentially with age shifting Th1/Th2 crossregulatory pressures and local expression of chemokines.
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PMID:Differential effects of ageing on cytokine and chemokine responses during type-1 (mycobacterial) and type-2 (schistosomal) pulmonary granulomatous inflammation in mice. 1174 43

Studies of SOCS-1-deficient mice have implicated Socs-1 in the suppression of JAK-STAT (Janus tyrosine kinase-signal transducers and activators of transcription) signaling and T cell development. It has been suggested that the levels of Socs-1 protein may be regulated through the proteasome pathway. Here we show that Socs-1 interacts with members of the Pim family of serine/threonine kinases in thymocytes. Coexpression of the Pim kinases with Socs-1 results in phosphorylation and stabilization of the Socs-1 protein. The protein levels of Socs-1 are significantly reduced in the Pim-1(-/-), Pim-2(-/-) mice as compared with wild-type mice. Similar to Socs-1(-/-) mice, thymocytes from Pim-1(-/-), Pim-2(-/-) mice showed prolonged Stat6 phosphorylation upon IL-4 stimulation. These data suggest that the Pim kinases may regulate cytokine-induced JAK-STAT signaling through modulation of Socs-1 protein levels.
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PMID:Pim serine/threonine kinases regulate the stability of Socs-1 protein. 1185 14


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