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)

The cellular infiltrates of certain inflammatory processes found in parasitic infection or in allergic diseases consist predominantly of eosinophilic granulocytes, often in association with activated T cells. This suggests the existence of chemotactic agonists specific for eosinophils and lymphocyte subsets devoid of neutrophil-activating properties. We therefore examined four members of the intercrine/chemokine superfamily of cytokines (monocyte chemotactic peptide 1 [MCP-1], RANTES, macrophage inflammatory protein 1 alpha [MIP-1 alpha], and MIP-1 beta), which do not activate neutrophils, for their ability to affect different eosinophil effector functions. RANTES strongly attracted normal human eosinophils by a chemotactic rather than a chemokinetic mechanism with a similar efficacy as the most potent chemotactic myeloid cell agonist, C5a. MIP-1 alpha also induced eosinophil migration, however, with lower efficacy. RANTES and MIP-1 alpha induced eosinophil cationic protein release in cytochalasin B-treated eosinophils, but did not promote leukotriene C4 formation by eosinophils, even after preincubation with interleukin 3 (IL-3), in contrast to other chemotactic agonists such as C5a and formyl-methionyl-leucyl-phenylalanine (FMLP). RANTES, but not MIP-1 alpha, induced a biphasic chemiluminescence response, however, of lower magnitude than C5a. RANTES and MIP-1 alpha both promoted identical transient changes in intracellular free calcium concentration ([Ca2+]i), with kinetics similar to those induced by chemotactic peptides known to interact with G protein-coupled receptors. No cross-desensitization towards other peptide agonists (e.g., C5a, IL-8, FMLP) was observed, suggesting the presence of specific receptors. Despite its weaker eosinophil-activating properties, MIP-1 alpha was at least 10 times more potent on a molar basis than RANTES at inducing [Ca2+]i changes. Interestingly, RANTES deactivated the MIP-1 alpha-induced [Ca2+]i changes, while the RANTES response was preserved after MIP-1 alpha stimulation. MCP-1, a potent monocyte chemoattractant and basophil agonist, as well as MIP-1 beta, a peptide with pronounced homology to MIP-1 alpha, did not activate the eosinophil functions tested. Our results indicate that RANTES and MIP-1 alpha are crucial mediators of inflammatory processes in which eosinophils predominate.
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PMID:RANTES and macrophage inflammatory protein 1 alpha induce the migration and activation of normal human eosinophil granulocytes. 128 Dec 7

A number of nuclearly encoded mitochondrial protein precursors that are transported into the matrix and inner membrane are cleaved in two sequential steps by two distinct matrix peptidases, mitochondrial processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP). We have isolated and purified MIP from rat liver mitochondrial matrix. The enzyme, purified 2250-fold, is a monomer of 75 kDa and cleaves all tested mitochondrial intermediate proteins to their mature forms. About 20% of the final MIP preparation consists of equimolar amounts of two peptides of 47 kDa and 28 kDa, which are apparently the products of a single cleavage of the 75 kDa protein. These peptides are not separable from the 75 kDa protein, nor from each other, under any conditions used in the purification. The peptidase has a broad pH optimum between pH 6.6 and 8.9 and is inactivated by N-ethylmaleimide (NEM) and other sulfhydryl group reagents. The processing activity is divalent cation-dependent; it is stimulated by manganese, magnesium or calcium ions and reversibly inhibited by EDTA. Zinc, cobalt and iron strongly inhibit MIP activity. This pattern of cation dependence and inhibition is not clearly consistent with that of any known family of proteases.
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PMID:Rat liver mitochondrial intermediate peptidase (MIP): purification and initial characterization. 132 90

Calcium-binding membrane-bound proteins are present in the vertebrate eye lens. Among these proteins are a distinct group of immunologically related extrinsic EDTA-extractable proteins (EEP) and calmodulin. The EEP proteins contain calcium-binding sites with a total capacity of 25 mol Ca2+ per mol protein. This high calcium-binding capacity of EEP points to a function of these proteins as intracellular calcium store in the lens. However, EEP undergoes a conformational change upon calcium binding, indicating that these proteins may be involved in the regulation of calcium-dependent cellular processes in the lens. One of these processes is the action of communicating lens fiber junctions, which contain EEP as a main protein component. In addition to EEP, another calcium-binding protein in lens, calmodulin, probably functions as mediator of calcium in the regulation of the structure and function of lens junctions. Like other vertebrate calmodulins, lens calmodulin shows a calcium-dependent mobility shift on SDS-polyacrylamide gels and forms immune complexes with antiserum raised against vertebrate calmodulin. Lens calmodulin binds to the junction proteins MIP (main intrinsic protein, MW 26 Kdalton) and a 17.5 Kdalton polypeptide of lens fiber cells in a calcium-independent manner. Via calmodulin the junctions become calcium-sensitive.
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PMID:Calcium-binding lens membrane proteins. 394 61

Human neutrophils at inflammatory sites may be an important source of the chemotactic cytokines macrophage inflammatory protein 1 alpha (M1P-1 alpha; a C-C chemokine) and interleukin 8 (IL-8; a C-X-C chemokine). In this study, we show that the inflammatory microcrystals monosodium urate monohydrate (MSU) and calcium pyrophosphate dihydrate (CPPD), the major mediators of gout and pseudogout, differentially regulate the production of these two chemokines by human neutrophils. Both MSU and CPPD increased the secretion of IL-8 by neutrophils in a dose- and time-dependent manner, but had no effect on that of MIP-1 alpha. Since inflammatory cytokines are likely to be present in the synovium during crystal-induced inflammation, we examined the interaction between TNF-alpha and GM-CSF and the crystals. Both TNF-alpha and GM-CSF stimulated IL-8 production; however, only TNF-alpha exerted a significant effect on MIP-1 alpha secretion in neutrophils. IL-8 production induced by TNF-alpha and GM-CSF was synergistically enhanced in the presence of MSU or CPPD, whereas MIP-1 alpha secretion induced by TNF was completely inhibited in the presence of either MSU or CPPD. Interestingly, no interaction between the crystals and the inflammatory cytokines was observed with respect to synthesis of the C-X-C chemokine MGSA in neutrophils. These results suggest that the combination of TNF-alpha and GM-CSF with MSU or CPPD will lead to the production of IL-8 by neutrophils and abolish the release of MIP-1 alpha, an event that will theoretically lead to recruitment of neutrophils but not mononuclear cells. These results are in accordance with the pathological state of gout and pseudogout, where the predominant inflammatory cell is the neutrophil.
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PMID:Inflammatory microcrystals differentially regulate the secretion of macrophage inflammatory protein 1 and interleukin 8 by human neutrophils: a possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. 750 47

Eosinophilic differentiation of a pro-eosinophilic HL-60 cell line resulted in the induction of a high affinity RANTES/macrophage inflammatory protein-1 alpha receptor. The induced receptor is biochemically indistinguishable in RANTES equilibrium-binding studies from the monocytic receptor expressed on THP-1 cell membranes. Continued expression of the receptor requires the continuous presence of the inducing stimulus, and receptor site number declines without a loss of binding affinity with a t1/2 of 11.5 h on withdrawal of the inducing stimulus. The induced receptor is capable of three physiologic measures of receptor coupling, namely, ligand-induced Ca2+ fluxes, priming of the respiratory burst, and chemotaxis. Dose-dependent Ca2+ fluxes were elicited upon increasing concentrations of RANTES and MIP-1 alpha whereas no response was measured upon addition of MIP-1 beta or MCP-1. In addition, desensitization studies demonstrated that previous exposure to either RANTES or MIP-1 alpha almost completely inhibits a Ca2+ flux upon subsequent exposure to either ligand. Priming of the respiratory burst to PMA in differentiated cells by human rRANTES was more effective than priming by IL-5 or granulocyte-macrophage-CSF, whereas undifferentiated cells failed to secrete superoxide anion. In addition, differentiated cells underwent chemotaxis in response to RANTES. This provides the first evidence for the induction of a C-C chemokine receptor upon eosinophilic differentiation of a leukocyte cell line, and is in keeping with the demonstrated ability of human RANTES to induce the rapid formation of eosinophilic inflammatory sites.
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PMID:Induction, characterization, and functional coupling of the high affinity chemokine receptor for RANTES and macrophage inflammatory protein-1 alpha upon differentiation of an eosinophilic HL-60 cell line. 751 65

The biological responses of human monocytes and cells of the monomyelocytic THP-1 cell line to stimulation with members of the beta chemokine family are described in this report. All three chemokines tested, MCP-1, MIP-1 alpha, and RANTES, elicited mobilization of intracellular free calcium in monocytes and THP-1 cells. The magnitude of response was highest with MCP-1 stimulation. MCP-1 desensitized monocyte responses to MIP-1 alpha and RANTES, but no such desensitization was observed in THP-1 cells. MIP-1 alpha or RANTES did not desensitize either monocytes or THP-1 cells to MCP-1 stimulation. All three chemokines elicited a potent chemotactic response in monocytes that was comparable in magnitude to that of f-Met-Leu-Phe. MIP-1 alpha and RANTES required a fivefold higher dose than MCP-1 to elicit a peak response. On the contrary, THP-1 cells showed no significant chemotactic response. Studies of the desensitization of the monocyte chemotactic response indicated that all three chemokines are capable of causing complete homologous desensitization. Heterologous desensitization was observed only when monocytes were treated with MCP-1 followed by MIP-1 alpha or RANTES. Studies of actin polymerization and cell polarization responses of monocytes indicated that these two responses attained peak magnitude after 10 min of stimulation with any of the chemokines. Dose-response kinetics were similar to those of the chemotactic response. THP-1 cells again failed to show either of these two responses. Finally, the activation potential of the chemokines was measured by their ability to induce respiratory burst. A tenfold higher concentration than that causing peak chemotactic response was required to elicit respiratory burst and no heterologous desensitization was noticed. Respiratory burst could be induced in THP-1 cells with a direct protein kinase C activator but not with any of the chemokines. These results indicate that, of the three examples tested, MCP-1 is the most potent member of the beta chemokine family in the biological responses examined. Although a calcium response was elicited in THP-1 cells with chemokines, a lack of subsequent responses indicates some missing links in the downstream signal transduction pathways.
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PMID:Comparison of biological responses of human monocytes and THP-1 cells to chemokines of the intercrine-beta family. 751 94

We report that responses of normal human eosinophils toward the chemokines RANTES and interleukin-8 (IL-8) are modulated and upregulated by priming with IL-5. In a modified Boyden chamber assay, we studied migratory responses toward the members of the chemokine family RANTES, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1 alpha (MIP-1 alpha) (C-C subfamily), and IL-8, platelet factor-4 (PF-4), and neutrophil-activating peptide-2 (NAP-2) (C-x-C subfamily). These chemokines were also studied in terms of actin polymerization and ([Ca2+]i)-mobilizing properties, intracellular signals that are thought to play a role during migratory responses. We found that eosinophils showed significant migratory responses toward RANTES and IL-8 at concentrations of 10(-9) to 10(-7) mol/L only after priming with IL-5 (10 pmol/L). At these concentrations, PF-4, NAP-2, MCP-1, and MIP-1 alpha induced no significant migratory responses after priming. Unprimed eosinophils only showed a significant migratory response toward RANTES (10(-6) mol/L). Changes in [Ca2+]i were found after addition of RANTES, MIP-1 alpha, and NAP-2 (10 nmol/L) to unprimed eosinophils. RANTES (10(-9) to 10(-7) mol/L) significantly induced actin polymerization both in primed and unprimed eosinophils, whereas IL-8 (10(-9) to 10(-8) mol/L) and MIP-1 alpha (10(-8) mol/L) only induced actin polymerization after priming with IL-5. NAP-2, PF-4, and MCP-1 did not affect actin polymerization. These findings are further evidence for the hypothesis that cytokines like IL-5 and locally secreted chemokines like RANTES and IL-8 are both at the basis of specific eosinophil influx into the allergic inflammatory locus.
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PMID:RANTES- and interleukin-8-induced responses in normal human eosinophils: effects of priming with interleukin-5. 751 18

In the present study we investigated the ability of three monocyte chemokines (MCP-1, MIP-1 alpha, and RANTES) to modulate monocyte adhesion molecules in an attempt to evaluate their potential to induce tissue infiltration of macrophages in vivo. All three chemokines tested induced increased expression of the alpha-chains of two members of beta 2 family of integrins, CD11b and CD11c, and their common beta-chain (CD18). They had no effect on CD11a expression. Enhancement of CD11b and CD11c was dose dependent and followed a distinct time course with peak levels at 4 h. Levels declined to reach basal levels by 24 h. In contrast, IL-1 induced enhancement remained high after 24 h of stimulation. However, the increases caused by chemokines were not mediated by IL-1 as indicated by lack of inhibition by the IL-1R antagonist. Studies on the mechanism of integrin up-regulation showed that mobilization of cytosolic free calcium is an important signaling event in this response and that up-regulation is associated with mobilization from intracellular pools mediated by microtubules. Enhanced CD11b and CD11c expression by chemokines was also found to result in enhancement of monocyte binding to endothelial cells. Further studies indicated that monocyte binding to endothelial cells follows similar dose-response kinetics as the up-regulation of integrins and can be partially blocked by Abs to CD11b and CD11c. These results suggest that modulation of the integrin expression by chemokines may facilitate the tissue trafficking of monocytes during inflammation.
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PMID:Regulation of monocyte integrin expression by beta-family chemokines. 752 13

The activities of six synthetic CC chemokines, MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta on human blood monocytes were studied. All CC chemokines elicited a bimodal migration response in vitro. Highest numbers of migrating cells were obtained with the monocyte chemotactic proteins (MCP) and RANTES, somewhat lower numbers with MIP-1 alpha, and only weak migration with MIP-1 beta. The most potent attractants were MCP-1 and MIP-1 alpha which reached maximum efficacy at 0.1 to 1 nM. All CC chemokines also induced the release of N-acetyl-beta-D-glucosaminidase from cytochalasin B-pretreated monocytes. The MCP were most effective (MCP-1 > MCP-3 > MCP-2), RANTES and MIP-1 alpha showed moderate (1/3 of MCP-1 activity), and MIP-1 beta only minimal activity. Cytosolic free Ca2+ changes and exocytosis were used to monitor receptor desensitization. Marked cross-desensitization was observed among MCP-1, MCP-2 and MCP-3 on the one hand, and RANTES, MIP-1 alpha and MIP-1 beta on the other, indicating receptor sharing within these two subgroups of CC chemokines. The responses to RANTES, MIP-1 alpha and MIP-1 beta were also moderately to markedly desensitized by pretreatment with MCP-1, MCP-2 or MCP-3, while the responses to the MCP were virtually unaffected by pretreatment with RANTES, MIP-1 alpha and MIP-1 beta. These results suggest that the MCP also interact with receptors recognized by RANTES, MIP-1 alpha and MIP-1 beta, but not vice versa. Binding studies were performed with radiolabeled MCP-1 or MIP-1 alpha. All MCP competed readily for labeled MCP-1 yielding a concentration-dependent sigmoidal displacement curve. Displacement with RANTES, MIP-1 alpha and MIP-1 beta was observed at higher concentrations, but was not complete. Radiolabeled MIP-1 alpha was displaced efficiently by MIP-1 alpha or MIP-1 beta, but only partially by RANTES. Of the MCP, only MC-3 completely displaced MIP-1 alpha, while only partial displacement was observed with MCP-1 and MCP-2.
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PMID:Actions of the chemotactic cytokines MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta on human monocytes. 753 Nov 49

Interleukin-8 (IL-8) is a member of the CXC branch of the chemokine superfamily and activates neutrophils but not monocytes. The related CC chemokine branch, which includes monocyte chemoattractant protein-1 (MCP-1) and RANTES are potent chemoattractants for monocytes but not neutrophils. Examination of the sequences of the CXC chemokines reveals that the highly conserved leucine, corresponding to Leu25 in IL-8, is always replaced by tyrosine in CC chemokines. There is also a high degree of conservation among the CXC chemokines of the adjacent Val27 residue, which points out from the same side of the beta-sheet as Leu25. In RANTES, Val27 is also replaced by a tyrosine. In order to investigate the role of these residues in controlling cell specificity, we have made the single mutants Leu25-->Tyr, Val27-->Tyr and the double mutant Leu25-->Tyr, Val27--> Tyr of IL-8. These proteins have been expressed in Escherichia coli and purified to homogeneity from inclusion body material. All three mutants have lower potency and efficacy in chemotaxis and calcium mobilization assays using neutrophils. The mutants also show lowered affinity to both IL-8 receptors A and B expressed recombinantly in HL-60 cells and to neutrophils in [125I]IL-8 competition assays. Additionally, the Leu25-->Tyr mutation introduces a novel monocyte chemoattractant activity into IL-8. We therefore studied the displacement of [125I]MIP-1 alpha by IL-8 Leu25-->Tyr from the CC-CKR-1 receptor. The mutant displaces MIP-1 alpha ligand with an affinity only 12-fold less than MIP-1 alpha itself. This suggests that mutations in this region of IL-8 are involved in receptor binding and activation and in the control of specificity between CC and CXC chemokines.
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PMID:Mutation of Leu25 and Val27 introduces CC chemokine activity into interleukin-8. 753 92


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