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)

Defensins are a family of microbicidal and cytotoxic peptides abundant in the lysosomal granules of mammalian phagocytes. We present the cDNA and genomic sequences of two rabbit defensins, macrophage cationic peptides MCP-1 and MCP-2. Their cDNA and genomic sequences are highly homologous, reflecting the homology between the two defensins (32 of 33 amino acids). The MCP genes are closely linked (within 13 kb) suggesting that they evolved by a recent tandem gene duplication. Their cDNA sequences indicate that the peptides are synthesized as 95 amino acid prepro-MCPs, consistent with their lysosomal location. The MCP genes are separated into three exons encoding distinct domains: the 5' untranslated region, the prepropeptide domain, and the mature defensin sequence. Fully developed polymorphonuclear leukocytes, short-lived phagocytes with limited capacity for protein and nucleic acid synthesis, contained MCPs but lacked MCP mRNA. MCP mRNA was found in bone marrow and spleen, organs which contained immature polymorphonuclear leukocytes. MCP and MCP mRNA were detected in lung macrophages, but not in macrophages from other organs, nor in monocytes, the putative macrophage precursors. In macrophages, the expression of MCPs appears to be a marker of lung-specific differentiation.
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PMID:The structure of the rabbit macrophage defensin genes and their organ-specific expression. 274 83

The interaction of the polycationic rabbit alveolar macrophage cationic proteins MCP-1 and MCP-2 (or their identical neutrophil equivalents NP-1 and NP-2) with the surface of Pseudomonas aeruginosa was investigated. Both proteins bound avidly to purified lipopolysaccharide, as judged by their ability to competitively displace the probe dansyl polymyxin with 50% inhibition (I50) values of 2 to 3 microM. Similar I50 were measured with dansyl polymyxin as a probe for cell surface binding, suggesting that the initial binding site for MCP-1 and MCP-2 on the surface of cells was lipopolysaccharide. Both MCP-1 and MCP-2 permeabilized outer membranes to the hydrophobic fluorescent probe 1-N-phenylnaphthylamine (NPN). The initial rate of NPN uptake plotted against the concentration of MCP-1 or MCP-2 gave sigmoidal curves, suggesting cooperative permeabilization of the outer membrane. Replotting the data as a Hill plot gave an affinity parameter, S0.5, the concentration of MCP giving a half-maximal increase in the rate of NPN uptake, of 5 and 25 microM for MCP-1 and MCP-2, respectively, and thus subsequent studies concentrated on the more active permeabilizer MCP-1. Permeabilization of outer membranes to NPN was a function of buffer pH, with lower pH considerably favoring the permeabilizing effects of MCP-1. Thin-section electron microscopic visualization of MCP-1-treated cells showed production of extended blebs. Further evidence of an altered cell surface after MCP-1 treatment was obtained by demonstrating that treated unopsonized cells were more efficiently phagocytosed by unelicited rabbit alveolar macrophages. The data overall suggest that macrophage cationic proteins interact with the P. aeruginosa outer membrane in a manner typical of other polycations and suggest that one of their major functions may be to permeabilize the outer membrane.
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PMID:Interaction of macrophage cationic proteins with the outer membrane of Pseudomonas aeruginosa. 312 11

Adult rabbit alveolar macrophages (AM) contain 2 cationic peptides with a broad spectrum of antimicrobial activity in vitro against bacteria, fungi, and some enveloped viruses. We determined the amounts of both peptides qualitatively in 1-day-old (1d), 7-day-old (7d), 21-day-old (21d), and adult rabbit AM and found that 1d AM were deficient in both peptides. The levels of MCP-1 extractable from AM were quantitated relative to known standards of purified peptides and were found to increase 6-fold between 1d and 21d AM. Adult AM yielded 9 times as much MCP-1 as did 1d AM despite nearly the same acid-extractable protein content per cell. Using immunoperoxidase techniques we showed that the deficiency of MCP-1 and MCP-2 involves 1d AM uniformly and that all AM 7 days or older have detectable MCP. Seven-day-old AM (and to a lesser extent 1d AM) incorporated 35S-cysteine into intracellular MCP in cell culture, indicating that AM actively synthesize these peptides. The deficiency of these antimicrobial substances may contribute to functional immaturity of newborn rabbit AM.
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PMID:Newborn rabbit alveolar macrophages are deficient in two microbicidal cationic peptides, MCP-1 and MCP-2. 405 25

It has been shown that CC chemokines activate basophil and eosinophil leukocytes with different selectivities and patterns of activity. The most effective are monocyte chemotactic protein-1 (MCP-1), a potent stimulus of mediator release in basophils without effects on eosinophils, RANTES, a weak stimulus of release and strong chemoattractant for basophils and eosinophils, and MCP-3, which combines the activities of MCP-1 and RANTES. We have now compared MCP-2, which has 62 and 60% of sequence identity with MCP-1 and MCP-3, respectively, with the other CC chemokines. MCP-2 induced mediator release by human basophils with lower efficacy and potency than MCP-1 and MCP-3. It promoted transient changes of cytosolic-free calcium concentration ([Ca2+]i) and chemotactic responses in both basophils and eosinophils, however somewhat less efficiently than MCP-3 and RANTES. Desensitization studies indicate that MCP-2 interacts with receptors recognizing MCP-1 as well as RANTES. These results demonstrate that MCP-2 and MCP-3 exert qualitatively similar biologic activities on basophils and eosinophils. In basophils that had not been treated with IL-3, MCP-2 induced minimal exocytosis only, but desensitized the cells toward MCP-1 and MCP-3, suggesting that MCP-2 may act as a functional inhibitor of CC chemokine actions. The results of this study further indicate that MCP analogues display partially distinct, partially overlapping bioactivities toward eosinophils and basophils, and may thus regulate inflammatory processes involving these effector cell types.
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PMID:Monocyte chemotactic protein MCP-2 activates human basophil and eosinophil leukocytes similar to MCP-3. 753 23

Madin Darby bovine kidney (MDBK) cells were used as a source to identify novel bovine chemotactic factors for granulocytes and monocytes. A major bovine granulocyte chemotactic protein (GCP-2) has previously been isolated. A novel bovine monocyte chemotactic protein (bo MCP) was produced on MDBK cells stimulated with phorbol ester. The 14-kDa protein was purified to homogeneity by adsorption to controlled pore glass, heparin affinity chromatography, cation-exchange FPLC, and RP-HPLC. The amino acid sequence of the NH2-terminally blocked protein was determined by Edman degradation using proteolytic fragments. The primary structure of the bo MCP, characterized by four conserved cysteines, allowed classification of the protein within the C-C chemokine family. Bo MCP-1B was most related to known human and bovine MCPs. Compared to bovine MCP-1 and MCP-2, the protein consists of 84% and 53% identical amino acids, respectively. Since this bo MCP was also most homologous to human and animal MCP-1, it was designated bo MCP-1B. The minimal effective dose of bo MCP-1B for monocyte chemotactic activity was 0.2 mM. The maximal migration index, reached at 2 nM, was comparable to that of natural human MCP-1. Furthermore, bo MCP-1B was found to be capable of stimulating beta-glucuronidase release from monocytes. In contrast, bo MCP-1B was not chemotactic for neutrophilic and eosinophilic granulocytes. By its biological and biochemical characteristics, bo MCP-1B has to be considered as an authentic additional MCP-1 chemokine. The existence of a possible human counterpart for this novel MCP-1B still needs to be elucidated.
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PMID:Purification, sequence analysis, and biological characterization of a second bovine monocyte chemotactic protein-1 (Bo MCP-1B). 794 49

MCP-1 is a small (8-10 KDa) protein and a prototype member of the CC chemokine beta subfamily, which plays a critical role in acute and chronic inflammation. Recent evidence suggests an important role for MCP- 1, MCP-2 and MCP-3 in a number of pathological states, including delayed type hypersensitivity conditions, parasitic infections and rheumatoid arthritis. Forty BALB-c mice were treated with the parasite Trichinella spiralis. After the infection the animals were sacrificed at different periods from the initial infection and MCP-1 and TNFalpha were quantified in the mouse serum. The level of MCP-1 in the serum of mice infected with 100 larvae increases from 27.5+/-7.0 pg/ml at day 23, to a maximum level of 31.5+/-5.0 pg/ml at day 33, then decreased to 14.6+/-2.0 pg/ml at day 47. When the mice were infected with 200 larvae of T. spiralis the maximum increase was 34.4+/-2.5 pg/ml found on day 23. From day 33 to day 47 MCP-1 levels were decreased. In addition, in infected mice levels of TNFalpha were detectable in the serum as early as day 1. The level of TNFalpha was maximum at day 35 (3812+/-224 pg/ml). Serum from non-infected mice contained no detectable levels of either MCP-1 or TNFalpha. However, even if MCP-1 seems to be implicated in Trichinellosis, its exact role and function in inflammatory parasitic diseases remains to be determined.
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PMID:Induction of monocyte chemotactic protein-1 (MCP-1) and TNF alpha by Trichinella spiralis in serum of mice in vivo. 954 42

To compare CC chemokine mRNA levels from native peripheral blood mononucleated cells (PBMCs) before and 6 months after the initiation of two different regimens of highly active antiretroviral therapy (HAART), we treated group 1 (n = 11) with two nucleoside analogues and the protease inhibitor (PI) indinavir boosted by ritonavir (800/100 mg b.i.d.); group 2 (n = 8) was treated with the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz instead of PI. CC chemokine mRNA levels (regulated upon T cell activation expressed secreted [RANTES], macrophage inhibitory protein [MIP]-1alpha, MIP-1beta, monocyte chemotactic protein [MCP]-1, MCP-2) were quantified from PBMCs before and 6 months after the initiation of HAART using a reverse transcription/real-time polymerase chain reaction (PCR) assay. The mRNA levels of MCP-1 and MCP-2 were significantly decreased in both groups (P < 0.05), while MIP-1alpha and MIP-1beta were decreased significantly only in the PI-treated group, but not in the NNRTI group. A moderate decrease of RANTES was observed in both treatment groups. The data suggest that HAART regimens containing either NNRTI or PI are not equivalent with regard to modification of CC chemokine mRNA profiles.
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PMID:Chemokine mRNA levels in mononucleated cells of HIV-infected patients before and after initiation of PI- versus NNRTI-containing HAART. 1516 2

Pulmonary alveolar proteinosis (PAP) is a rare autoimmune lung disease characterized by abnormal surfactant accumulation within alveolar macrophages, and circulating auto-antibodies against granulocyte-macrophage colony stimulating factor (GM-CSF) resulting in functional GM-CSF deficiency. Monocyte/macrophage chemotactic protein-1 (MCP-1) is elevated in PAP, suggesting association with the pathophysiology. Because PAP has been associated with inflammatory pulmonary changes, we hypothesized that other MCP family chemokines would be present and that Chemokine Chemotaxis Receptor 2 (CCR2) would be elevated on PAP mononuclear cells. Here we show for the first time that MCP-2 and MCP-3, like MCP-1, are highly elevated in PAP. We also confirm that PAP alveolar macrophages and not epithelial cells produce MCP-1, and that MCP-1 from PAP lung has functional chemoattractant activity. Surprisingly, CCR2 expression is diminished in PAP lymphocytes and alveolar macrophages compared to controls. Further, MCP-1 from PAP lung suppresses CCR2 expression in vitro, suggesting that in PAP, MCP-1 participates in an autocrine regulatory network in vivo.
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PMID:Elevated monocyte chemotactic proteins 1, 2, and 3 in pulmonary alveolar proteinosis are associated with chemokine receptor suppression. 1559 12

Changes in circulating cytokines might serve as predictors of compound-evoked inflammatory responses. CD-1 mice were treated with lipopolysaccharide (LPS; 0.2 ml of 0.25 mg/ml, intraperitoneal) for subsequent expression measurement of plasma cytokine protein expression at 24-h post-treatment using multiple antibody Western blot, and at both 2-h and 24-h post-treatment using antibody array and suspension bead array. Antibody array provided a semi-qualitative assessment and suggested significantly increased expression of GCSF at 2-h post-treatment and GCSF, IL-6, IL-12, MCP-1, MCP-5, RANTES and sTNFR1 at 24-h post-treatment. Densitometric analysis of multiple antibody Western blots provided a semi-quantitative assessment and indicated significantly increased expression of IL-6, IL-12, IL-17, GCSF, eotaxin, and MCP-2 at 24-h post-treatment. The suspension bead array yielded statistically significant cytokine protein expression increases for IL-6, IL-10, IFNgamma and TNFalpha at both 2-h and 24-h post-treatments, while significant expression at 24-h post-treatment only was noted for IL-1beta, IL-5, IL-12 and GM-CSF. Suspension bead array provided the greatest range of detection, revealing subtle increased expression of GM-CSF, IL-1beta, IL-5, IL-10, TNFalpha and IFNgamma at 24-h post-treatment, not detected by antibody array or multiple antibody Western blot. Suspension bead array proved to be the best method for detection of LPS-evoked changes in plasma cytokine levels.
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PMID:Comparative methods for multiplex analysis of cytokine protein expression in plasma of lipopolysaccharide-treated mice. 1625 31

IL-13 is an important stimulator of inflammation and tissue remodeling at sites of Th2 inflammation, which plays a key role in the pathogenesis of a variety of human disorders. We hypothesized that the ubiquitous transcription factor, early growth response-1 (Egr-1), plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of Egr-1 and related moieties in lungs from wild type mice and transgenic mice in which IL-13 was overexpressed in a lung-specific fashion. We simultaneously characterized the effects of a null mutation of Egr-1 on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 stimulates Egr-1 via an Erk1/2-independent Stat6-dependent pathway(s). They also demonstrate that IL-13 is a potent stimulator of eosinophil- and mononuclear cell-rich inflammation, alveolar remodeling, and tissue fibrosis in mice with wild type Egr-1 loci and that these alterations are ameliorated in the absence of Egr-1. Lastly, they provide insights into the mechanisms of these processes by demonstrating that IL-13 stimulates select CC and CXC chemokines (MIP-1alpha/CCL-3, MIP-1beta/CCL-4, MIP-2/CXCL2/3, MCP-1/CCL-2, MCP-2/CCL-8, MCP-3/CCL-7, MCP-5/CCL-12, KC/CXCL-1, and Lix/CXCL-5), matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and apoptosis regulators (caspase-3, -6, -8, and -9 and Bax) and activates transforming growth factor-beta1 and pulmonary caspases via Egr-1-dependent pathways. These studies demonstrate that Egr-1 plays a key role in the pathogenesis of IL-13-induced inflammatory and remodeling responses.
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PMID:Role of early growth response-1 (Egr-1) in interleukin-13-induced inflammation and remodeling. 1643 63


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