Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of focal brain damage as a trigger for autoimmune inflammation in multiple sclerosis (MS) is unclear. In this study we examine mechanisms by which experimental autoimmune encephalomyelitis (EAE) is enhanced by focal brain damage. EAE was produced in Lewis rats by footpad inoculation; focal brain damage, in the form of a cortical cryolesion (cryolesion-EAE), was induced 8 days post-inoculation (d.p.i.). The distribution of inflammation and chemokine production in cryolesion-EAE and EAE-only were compared. Inflammation in the brain, measured by immunocytochemistry for T lymphocytes (W3/13) and microglial activation (MHC class II -OX6), was significantly enhanced in cryolesion-EAE 11-15 d.p.i. (p < 0.01-0.05) but by 20-40 d.p.i., equated with EAE-only. Inflammation in cryolesion-EAE related to breakdown of the blood-brain barrier (BBB) at the site of the cryolesion and also to the corticospinal tracts and thalamus, reflecting the afferent and efferent neuronal connections with the cryolesioned cortex. Semiquantitative RT/PCR dot-blot hybridization assay showed a 6-fold increase in mRNA for specific chemokines in the brain in cryolesion-EAE at 9 d.p.i. (MCP-1) and 11 d.p.i. (MCP-1 and MCP-5) with no significant increase in RANTES, GRO-alpha, or MIP-1alpha. By 14 d.p.i., the levels of MCP-1 and MCP-5 mRNA equated with EAE-only animals. These results suggest that enhancement and location of autoimmune inflammation in the brain following focal cortical injury initially involve chemokines such as the macrophage chemoattractants MCP-1 and MCP-5, and the activities of afferent and efferent neuronal connections with the site of damage. By analogy, similar factors may modulate or reactivate autoimmune inflammation in MS.
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PMID:Role of chemokines, neuronal projections, and the blood-brain barrier in the enhancement of cerebral EAE following focal brain damage. 1113 23

DC (dendritic cells) represent an heterogeneous family of cells which function as sentinels of the immune system. They traffic from the blood to the tissues where, while immature, they capture antigens. Then, following inflammatory stimuli, they leave the tissues and move to the draining lymphoid organs where, converted into mature DC, they prime naive T cells. The key role of DC migration in their sentinel function led to the investigation of the chemokine responsiveness of DC populations during their development and maturation. These studies have shown that immature DC respond to many CC and CXC chemokines (MIP-1 alpha, MIP-1 beta, MIP-3 alpha, MIP-5, MCP-3, MCP-4, RANTES, TECK and SDF-1) which are inducible upon inflammatory stimuli. Importantly, each immature DC population displays a unique spectrum of chemokine responsiveness. For examples, Langerhans cells migrate selectively to MIP-3 alpha (via CCR6), blood CD11c+ DC to MCP chemokines (via CCR2), monocytes derived-DC respond to MIP-1 alpha/beta (via CCR1 and CCR5), while blood CD11c- DC precursors do not respond to any of these chemokines. All these chemokines are inducible upon inflammatory stimuli, in particular MIP-3 alpha, which is only detected within inflamed epithelium, a site of antigen entry known to be infiltrated by immature DC. In contrast to immature DC, mature DC lose their responsiveness to most of these inflammatory chemokines through receptor down-regulation or desensitization, but acquire responsiveness to ELC/MIP-3 beta and SLC/6Ckine as a consequence of CCR7 up-regulation. ELC/MIP-3 beta and SLC/6Ckine are specifically expressed in the T-cell-rich areas where mature DC home to become interdigitating DC. Altogether, these observations suggest that the inflammatory chemokines secreted at the site of pathogen invasion will determine the DC subset recruited and will influence the class of the immune response initiated. In contrast, MIP-3 beta/6Ckine have a determinant role in the accumulation of antigenloaded mature DC in T cell-rich areas of the draining lymph node, as illustrated by recent observations in mice deficient for CCR7 or SLC/6Ckine. A better understanding of the regulation of DC trafficking might offer new opportunities of therapeutic interventions to suppress, stimulate or deviate the immune response.
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PMID:Dendritic cell biology and regulation of dendritic cell trafficking by chemokines. 1115 41

Chemokines play an essential role in immune and inflammatory reactions via the recruitment of leukocytes. Studying the role of chemokines in vivo is complicated by the redundancy of their action and by their promiscuous receptor usage. The simultaneous analysis of several chemokines is, therefore, advantageous in order to obtain a comprehensive view of chemokine participation in inflammatory and infectious processes. At present, no multi-probe detection systems are available for the analysis of recently described chemokines. In this study, new multi-probe RNase protection assay (RPA) template sets were developed for the analysis of murine chemokines. Chemokine cDNA fragments were generated by RT-PCR and individually subcloned into the plasmid pGEM-T providing a T7 promotor. In this way, two multi-probe template sets were constructed each containing six chemokine sequences (CXCL12/SDF-1, XCL1/lymphotactin, CCL20/exodus-1, CCL25/TECK, CX3CL1/fractalkine, CXCL1/KC, and CCL20/MDC, CXCL9/MIG, CCL9/10/MIP-1gamma, CXCL13/BLC, CCL12/MCP-5, CCL19/ELC, respectively) and templates for the two house-keeping genes L32 and GAPDH. The evaluation of these RPA template sets in various murine models demonstrated their suitability for the analysis of the above chemokines both under constitutive and infection-induced conditions. To reduce the personal radiation hazard, we found that 32P could be replaced by 33P without any loss of assay-sensitivity. These new RPA multi-probe sets provide valuable tools for the simultaneous quantitative determination of gene expression of multiple murine chemokines of both constitutive and inducible type.
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PMID:Novel multi-probe RNase protection assay (RPA) sets for the detection of murine chemokine gene expression. 1122 73

This review will discuss the recent literature on the molecular mechanism of NF-kappaB activation, with special focus on IkappaB alpha dynamism involved in iNOS- and chemokine-induction in glial cells. NF-kappaB, a heterotrimer composed of p50, p65 (Rel A) and IkappaB alpha, has been shown to be activated by elimination of the regulatory subunit IkappaB alpha from the heterotrimer. The elimination of IkappaB alpha (formation of active NF-kappaB, p50-p65) is due to phosplorylation of serines 32 and 36 of IkappaB alpha, followed by polyubiquitination and 26S proteasomal degradation of IkappaB alpha. Experiments using stable clones of rat C6 glioma cells transfected with dominant negative IkappaB alpha (serines 32 and 36 replaced by alanine) suggest that NF-kappaB activation (phosphorylation of IkappaB alpha) is involved in LPS/IFNgamma- or IL-1beta/IFNgamma-induced iNOS expression. Furthermore, the time courses of phosphorylation, ubiquitination of IkappaB alpha and proteasome activity after IL-1beta treatment also suggest that 26S proteasomal degradation of IkappaB alpha is more crucial for chemokine expression in glial cells.
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PMID:NF-kappaB activation and IkappaB alpha dynamism involved in iNOS and chemokine induction in astroglial cells. 1127 Jun 16

Activation of NF-kappaB and production of NF-kappaB-dependent chemokines are thought to be involved in the pathogenesis of neutrophilic lung inflammation. Calpain-1 inhibitor (CI-1) blocks activation of NF-kappaB by preventing proteolysis of the inhibitory protein IkappaB-alpha by the ubiquitin/proteasome pathway. We hypothesized that inhibition of proteasome function with CI-1 would block NF-kappaB activation in vivo after intraperitoneal (i.p.) treatment with bacterial lipopolysaccharide (LPS), and that NF-kappaB inhibition would be associated with suppression of chemokine gene expression and attenuation of neutrophilic alveolitis. We treated rats with a single i.p. injection of CI-1 (10 mg/kg) two hours prior to i.p. LPS (7 mg/kg). Treatment with Cl-1 prevented degradation of IkappaB-alpha and activation of NF-kappaB in the liver in response to LPS; however, Cl-1 treatment had no detected effect on NF-kappaB activation in lung tissue. CI-1 treatment prior to LPS resulted in 40% lower MIP-2 concentration in lung lavage fluid compared to rats treated with vehicle prior to LPS (502 +/- 112 pg/ml vs. 859 +/-144 pg/ml, P < 0.05). In addition, CI-1 treatment substantially inhibited LPS-induced neutrophilic alveolitis (2.7+ /- 1.2 x 10(5) vs. 43.7 +/- 12.2 x 10(5) lung lavage neutrophils, P < 0.01). These data indicate that NF-kappaB inhibition in the liver can alter lung inflammation induced by systemic LPS treatment and suggest that a liver-lung interaction contributes to the inflammatory response of the lung.
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PMID:Suppression of lung inflammation in rats by prevention of NF-kappaB activation in the liver. 1129 63

Chemokines and adhesion molecules such as integrins play a major part in the trafficking, extravasation, and recruitment of leukocytes to inflammatory sites. This study investigated the effects of beta(2) integrin engagement on chemokine production by freshly isolated human monocytes. We found that ligation of CD11b or CD11c but not CD11a alpha chains of beta(2) integrins by antibodies or soluble CD23 (sCD23) fusion proteins rapidly induced transcription and secretion of interleukin 8, macrophage inflammatory protein (MIP) 1alpha, and MIP-1beta. Because the promoters of these chemokine genes contain kappaB binding sites, we assessed the possible role of nuclear factor-kappaB (NF-kappaB) in controlling induction of the genes through beta(2) integrin engagement. Electrophoretic mobility shift assays showed that sCD23 or antibodies to CD11b or to CD11c up-regulated DNA-binding activity of NF-kappaB. Activation of NF-kappaB was accompanied by degradation of its cytosolic inhibitor IkappaB-alpha. Blockade of depletion of IkappaB-alpha by proteasome inhibitors (proteasome inhibitor I or acetyl-leucinyl-leucinyl-norleucinal) led to concomitant inhibition of NF-kappaB DNA-binding activity and expression of MIP-1alpha and MIP-1beta messenger RNA induced by beta(2) integrin ligation. These results suggest that triggering of CD11b or CD11c beta(2) integrin on primary human monocytes provides activation signals leading to nuclear translocation of NF-kappaB and subsequent secretion of MIP-1alpha and MIP-1beta that may have an important role in recruitment of other inflammatory cells during initiation of an inflammatory response.
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PMID:Ligation of CD11b and CD11c beta(2) integrins by antibodies or soluble CD23 induces macrophage inflammatory protein 1alpha (MIP-1alpha) and MIP-1beta production in primary human monocytes through a pathway dependent on nuclear factor-kappaB. 1134 14

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

Monocyte chemotactic protein-3 (MCP-3) belongs to the MCP subgroup of CC chemokines that are structurally closely related but, which differ in receptor usage and hence in biological activities. MCP-3 is one of the most pluripotent chemokines since it activates all types of leukocytes, by binding to at least four different chemokine receptors. The natural protein is heterogeneous due to glycosylation and NH2-terminal processing. Only small amounts of MCP-3 are induced in various cell types by endogeneous (cytokines) or exogeneous (bacteria, viruses) agents. Nevertheless, this omnipotent chemokine, inducible in most body compartments, might play an important role in normal homeostasis as well as in various pathologies including cancer, auto-immune diseases and chronic inflammation.
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PMID:Monocyte chemotactic protein-3. 1178 Nov 81

Chemokines and their receptors play a critical role in host immune surveillance and are important mediators of human immunodeficiency virus (HIV) pathogenesis and inflammatory response. The chemokine receptors CCR5 and CXCR4, which act as co-receptors along with CD4 for HIV docking and entry, are down-modulated by their respective ligands, MIP-1beta/SDF-1alpha or by the HIV envelope protein, gp120. We have studied the role of the proteasome pathway in the down-regulation of these receptors. Using the yeast and mammalian two-hybrid systems, we observed that the CCR5 receptor is constitutively associated with the zeta subunit of proteasome. Immunoprecipitation studies in CCR5 L1.2 cells revealed that this association was increased with MIP-1beta stimulation. The proteasome inhibitors, lactacystin and epoxomicin, attenuated MIP-1beta induced CCR5 down-modulation as detected by fluorescence-activated cell sorter analysis and confocal microscopy. The proteasome inhibitors also inhibited the SDF-1alpha and gp120 protein-induced down-modulation of the CXCR4 receptor in Jurkat cells. However, the inhibitors had no significant effect on the gp120-induced internalization of the CD4 receptor. These inhibitors also blocked cognate ligand-mediated chemotaxis but had no effect on SDF-1alpha-induced p44/42 MAP kinase or MIP-1beta-induced p38 kinase activities, thus indicating differential effects of the inhibitors on signaling mediated by these receptors. These results indicate that the CCR5 and CXCR4 receptor down-modulation mechanism and chemotaxis mediated by these receptors are dependent upon proteasome activity.
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PMID:CXCR4/CCR5 down-modulation and chemotaxis are regulated by the proteasome pathway. 1187 45

Chemokines have emerged as critical regulators of leukocyte function and as such represent attractive new targets for the therapy of allergic diseases. Recent studies have revealed important roles for the chemokine family in both the afferent and efferent limbs of the immune system, orchestrating and integrating innate and acquired immune responses. A subset of chemokines including eotaxin-1 (also called CCL11), eotaxin-2 (CCL24), eotaxin-3 (CCL26), MCP (monocyte chemoattractant protein)-3 (CCL7), MCP (monocyte chemoattractant protein)-4 (CCL13), TARC (thymus- and activation-regulated chemokine) (CCL17), and MDC (macrophage-derived chemokine) (CCL22) are highly expressed in allergic inflammation and are regulated by T helper type 2 cytokines. Receptors for these chemokines, including CCR3 (CC chemokine receptor 3), CCR4 (CC chemokine receptor 4) and CCR8 (CC chemokine receptor 8) are expressed on key leukocytes associated with allergic inflammation, such as T helper type 2 cells, eosinophils, mast cells and basophils, establishing a subset of chemokine/chemokine receptors potentially important in allergic inflammation. Recent data using inhibitory antibodies and chemokine antagonists support the concept that interfering with this subset of chemokines and their receptors represents a new approach to allergy immunotherapy.
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PMID:Antichemokine immunotherapy for allergic diseases. 1196 42


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