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)

Thrombosis and inflammation are closely related. However, the response of the vein wall to venous thrombosis has been poorly documented. This study examines the hypothesis that venous thrombosis is associated with an inflammatory response in the vein wall. In a rat model of inferior vena caval thrombosis, vein wall was temporally examined for inflammation by assessment of histopathology, leukocyte morphometrics, and cytokine levels. Animals were killed 1 hour and 1, 3, and 6 days after thrombus induction. Our findings demonstrated an early (day 1) neutrophil infiltration into the vein wall followed by a later (days 3 and 6) monocyte/macrophage and lymphocyte response. Cytokines were elevated only under conditions of venous thrombosis. Levels of epithelial neutrophil activating protein-78 (ENA-78), tumor necrosis factor-alpha (TNF), interleukin-6, and JE/monocyte chemoattractant protein-1 (JE/MCP-1) increased over the 6-day period, while macrophage inflammatory protein-1 alpha (MIP-1 alpha) peaked at day 3 after thrombus induction. Additionally, rats were passively immunized with neutralizing antibodies to TNF, ENA-78, MIP-1 alpha, JE/MCP-1, intercellular adhesion molecule-1 (ICAM-1), and CD18 compared with control antibodies. The most effective antibody early after thrombus induction for attenuating vein wall neutrophil extravasation was anti-TNF (P < .01). The monocyte/macrophage extravasation was inhibited most by anti-ICAM-1 followed by anti-TNF (P < .01). These findings demonstrate that venous thrombosis is associated with significant vein wall inflammation that is partially inhibited by neutralizing antibodies to cytokines and adhesion molecules.
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PMID:Venous thrombosis-associated inflammation and attenuation with neutralizing antibodies to cytokines and adhesion molecules. 774 35

In the present study, we investigated the ability of the tetrapeptide NAc-Ser-Asp-Lys-Pro-OH (AcSDKP), a reported inhibitor of primitive hematopoietic cells, to influence the proliferative behavior of primitive normal and chronic myeloid leukemia (CML) progenitor cells in the adherent layer of long-term cultures (LTCs). Addition of > or = 50 ng/mL of AcSDKP to LTCs of normal cells at the time of the regular weekly half-medium change selectively and reversibly decreased the proportion of high proliferative potential erythroid and granulopoietic progenitors in the adherent layer that were in S-phase without changing their numbers, but had no effect on either the cycling activity or number of analogous (neoplastic) cells in the adherent layer of CML LTCs. Specificity of the effect of AcSDKP on primitive normal progenitors was demonstrated by the finding that a similar addition of either the control peptide, AcSDKE, or 100 ng/mL of tumor necrosis factor-alpha (TNF-alpha, which contains the SDKP sequence), or SDKP itself (at 300 ng/mL) did not inhibit the proliferation of primitive normal progenitors in LTC adherent layers. Incorporation of > or = 30 ng/mL of AcSDKP (but not the related control peptide, AcSDKE) directly into methylcellulose cultures of normal marrow cells resulted in a dose-dependent suppression of colony formation, which was not seen in similar studies with CML marrow or after removal of adherent cells from normal marrow. Additional experiments showed that the inhibitory effect of AcSDKP on primitive normal progenitor cycling in the LTC system could be overcome by the simultaneous addition of macrophage inflammatory protein-1 beta (MIP-1 beta); an antagonist of MIP-1 alpha. The apparent differential effect of AcSDKP on primitive normal and CML progenitors may thus be a secondary consequence of the differential responsiveness of these cells to MIP-1 alpha for another molecule antagonized by MIP-1 beta), whose production or release by adherent marrow cells is inducible by AcSDKP. Such a mechanism may offer a method for obtaining localized increases in vivo of cytokines like MIP-1 alpha, suggesting novel and perhaps less toxic strategies for protecting primitive normal progenitors during repeated treatments with cycle-active chemotherapeutic agents where escalating the dose of drug given would be desirable.
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PMID:The tetrapeptide AcSDKP specifically blocks the cycling of primitive normal but not leukemic progenitors in long-term culture: evidence for an indirect mechanism. 806 44

Using a rat model of acute lung inflammation induced by intratracheal instillation of lipopolysaccharide (LPS), we investigated the kinetics of mRNA expression and the potential cellular sources of tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2), interleukin (IL)-1 beta, IL-6, RANTES, and transforming growth factor-beta 1 (TGF-beta 1). By Northern blot analysis, TNF-alpha and MIP-2 mRNAs in total lung tissue increased markedly by 30 min and peaked by 1 h after LPS exposure, whereas expression of IL-1 beta and IL-6 was not detected until 1 h and peaked within 6 h. In contrast, neither RANTES nor TGF-beta 1 mRNA was induced by LPS throughout 72 h, although a basal expression was detected in both saline- and LPS-treated lung tissues. At 1 h after LPS, the bronchoalveolar lavage (BAL) fluid contained about 98% alveolar macrophages (AM), whereas by 6 or 12 h, 88% of BAL cells were polymorphonuclear neutrophils (PMN). Upon extraction of total RNA after separation of AM from PMN in BAL, Northern analysis showed that at 1 h, AM expressed pronounced signals for TNF-alpha, MIP-2, IL-1 beta, and IL-6. At 6 and 12 h, however, while cytokine transcripts decreased in AM, PMN exhibited strong signals for these cytokines. A low basal noninducible signal for TGF-beta 1 but not RANTES was detected in both AM and PMN. Finally, by in situ hybridization techniques, PMN in the lung tissue, particularly those located in the vicinity of the bronchiole and vasculature, were demonstrated to localize MIP-2 mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factor-alpha, macrophage inflammatory protein-2, interleukin-1 beta, and interleukin-6 but not RANTES or transforming growth factor-beta 1 mRNA expression in acute lung inflammation. 811 Apr 70

We have shown that human macrophages (m phi s) play an important role in the elaboration of chemotactic cytokines in rheumatoid arthritis (RA) (Koch, A. E., S. L. Kunkel, J. C. Burrows, H. L. Evanoff, G. K. Haines, R. M. Pope, and R. M. Strieter. 1991. J. Immunol. 147:2187; Koch, A. E., S. L. Kunkel, L. A. Harlow, B. Johnson, H. L. Evanoff, G. K. Haines, M. D. Burdick, R. M. Pope, and R. M. Strieter. 1992. J. Clin. Invest. 90:772; Koch, A. E., P. J. Polverini, S. L. Kunkel, L. A. Harlow, L. A. DiPietro, V. M. Elner, S. G. Elner, and R. M. Strieter. 1992. Science (Wash. DC). 258:1798). Recently, m phi inflammatory protein-1 (MIP-1 alpha), a cytokine with chemotactic activity for m phi s and neutrophils (PMNs), has been described. We have examined the production of MIP-1 alpha using sera, synovial fluid (SF), and synovial tissue (ST) from 63 arthritic patients. MIP-1 alpha was higher in RA SF (mean, 29 +/- 8 ng/ml [SE]) compared with other forms of arthritis (2.8 +/- 1.7), or osteoarthritis (0.7 +/- 0.4; P < 0.05). RA SF MIP-1 alpha was greater than that found in either RA or normal peripheral blood (PB) (P < 0.05). Anti-MIP-1 alpha neutralized 36 +/- 3% (mean +/- SE) of the chemotactic activity for m phi s, but not PMNs, found in RA SFs. RA SF and PB mononuclear cells produced antigenic MIP-1 alpha. Mononuclear cell MIP-1 alpha production was augmented with phytohemagglutinin or LPS. Isolated RA ST fibroblast production of antigenic MIP-1 alpha was augmented upon incubation of cells with LPS, and to a lesser extent with tumor necrosis factor-alpha. Isolated RA ST m phi s expressed constitutive MIP-1 alpha mRNA and antigenic MIP-1 alpha. Using ST immunohistochemistry, MIP-1 alpha+ cells from RA compared with normal were predominantly m phi s and lining cells (P < 0.05). These results suggest that MIP-1 alpha plays a role in the selective recruitment of m phi s in synovial inflammation associated with RA.
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PMID:Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. 813 78

The formation of hepatic granulomas around persistently deposited Schistosoma mansoni eggs leads to parenchymal damage, ongoing fibrosis, and ultimate loss of liver function. In this study, the production of macrophage inflammatory protein-1 alpha (MIP-1) and monocyte chemoattractant protein-1 (MCP-1) by granuloma fibroblasts was examined to establish the potential contribution of intragranuloma fibroblasts to the maintenance of the chronic inflammation. Isolated fibroblasts from dispersed acute infection hepatic granulomas were grown in tissue culture for 3 to 4 weeks and used on the third or fourth passage. We initially surveyed fibroblasts for production of MIP-1 and MCP-1 by reverse transcription-polymerase chain reaction (RT-PCR) after stimulation with interleukin (IL)-1, tumor necrosis factor, interferon (IFN)-gamma, IL-4, or IL-10: cytokines found within the granuloma. These studies demonstrated constitutive expression of MCP-1 and differential up-regulation of MIP-1 on cytokine stimulation. Protein expression was then verified by immunohistochemical localization of MIP-1 and MCP-1 in paraformaldehyde-fixed fibroblasts and by direct quantitation of MIP-1 and MCP-1 in culture supernatants by specific ELISAs. These studies demonstrated constitutive expression of MCP-1 in unstimulated and cytokine-stimulated granuloma fibroblasts. In contrast, IL-1 (0.1 to 2.5 ng/ml), IFN-gamma (10 micrograms/ml), and IL-10 (2.5 to 10 ng/ml) were able to induce the significant production of MIP-1 by the granuloma fibroblasts. Interestingly, normal noninflammatory fibroblasts from uninfected mice showed no significant production of MIP-1 or MCP-1 in response to these cytokines. These results suggest that granuloma fibroblasts may be phenotypically altered compared with normal fibroblasts and have a significant role in leukocyte recruitment, granuloma growth, and maintenance of the egg-induced lesion.
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PMID:Production of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 alpha by inflammatory granuloma fibroblasts. 816 Jul 72

The mixed lymphocyte reaction (MLR) has previously been used to elucidate pathways of cytokine activation and T-lymphocyte proliferation and is regarded as a model that simulates responses in allograft rejection. Studies have indicated that interleukin-1 (IL-1), a potent inflammatory cytokine, may have an important activating role in the MLR response. The discovery of a naturally occurring IL-1 receptor antagonist protein (IRAP) has renewed interest in control of IL-1--dependent responses both in vitro and in vivo. MLR cultures were used to study the role of IL-1 and IRAP in the regulation of subsequent cytokines during a T-lymphocyte-mediated alloantigen response. The temporal expression of IL-1 and IRAP during 5-day one-way MLR assays suggested antagonistic production of the two cytokines. IL-1 was produced early in the response, peaking at 4 hours through day 2, subsequently declining to near-background levels on day 5 of culture. In contrast, production of IRAP was delayed until day 2, steadily increased on days 3 and 4, and peaked on day 5 of culture, which correlated with the declining levels of IL-1. The addition of graded doses of IRAP (25 to 1,000 ng/mL) to MLR cultures decreased IL-1 production but had no effect on T-lymphocyte proliferative response. In addition, IRAP had little effect on the production of either IL-2 or tumor necrosis factor. The addition of 25 ng/mL of IRAP to MLR assays showed significantly decreased levels of two potent chemotactic cytokines, IL-8 and macrophage inflammatory protein-1 alpha (MIP-1 alpha), at peak chemokine production on day 5 of culture. The levels of IL-8 and MIP-1 alpha could be restored by the addition of IL-1 to the IRAP-treated cultures. IL-8 and MIP-1 alpha represent the two different families of chemotactic cytokines, C-X-C (IL-8) and C-C (MIP-1 alpha), and potentially play important roles in the recruitment of leukocytes to a site of immune allogeneic response. These studies indicate that regulation of IL-1 by IRAP does not significantly reduce T-lymphocyte activation but can regulate the production of chemokines involved in leukocyte recruitment.
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PMID:Interleukin-1 receptor antagonist blocks chemokine production in the mixed lymphocyte reaction. 826 Jul 4

Macrophage inflammatory proteins 1 alpha and 2 (MIP-1 alpha, MIP-2) are members of a growing family of cytokines thought to play a role in host defense. MIP-1 alpha and MIP-2 were previously identified in the mouse and shown to stimulate inflammatory cell recruitment. To better understand the potential role of MIP-1 alpha and MIP-2 in lung defense, we investigated the ability of rat lung cells to express mRNA for and/or secrete MIP-1 alpha and MIP-2 proteins in vitro and characterized expression of these cytokines in rat lung after in vivo exposure to silica (SiO2) or titanium dioxide (TiO2). In response to lipopolysaccharide, rat alveolar macrophages expressed increased levels of MIP-1 alpha and MIP-2 mRNA and secreted proteins (identified by N-terminal sequencing) homologous to mouse MIP-1 alpha and MIP-2. Rat alveolar macrophage MIP-1 alpha and MIP-2 mRNA expression was also increased by tumor necrosis factor-alpha (TNF) and adherence to plastic. Studies with a rat fibroblast and epithelial cell line demonstrated that MIP-2, but not MIP-1 alpha, expression can be detected in these cells after stimulation with TNF. Intratracheal instillation studies with SiO2 and TiO2 showed that inflammatory doses of these dusts increase MIP-1 alpha and MIP-2 mRNA expression in whole lung and that increased gene expression preceded the accumulation of inflammatory cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Macrophage inflammatory proteins 1 and 2: expression by rat alveolar macrophages, fibroblasts, and epithelial cells and in rat lung after mineral dust exposure. 838 10

A unique subset of gamma delta T cells, termed dendritic epidermal T cells (DETC), resides in symbiosis with keratinocytes in mouse epidermis. We have shown previously that interleukin 7 (IL-7) which is produced by keratinocytes, promotes growth and prevents apoptosis in DETC. To extend this observation, we examined 12 cytokines, each of which is expressed by epidermal cells at mRNA and/or protein levels, for their capacities to modulate the growth of DETC. Cytokines examined included IL-1 alpha, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma), granulocyte/macrophage-colony stimulating factor (GM-CSF), and macrophage inflammatory protein-1 alpha (MIP-1 alpha). When tested individually, IL-2 and IL-7 promoted maximal growth of the long-term cultured DETC line 7-17. When tested in combinations, synergistic growth-promoting effects were seen with IL-2 and IL-4 or IL-7, and with IL-7 and IL-4 or TNF alpha. Dose-response experiments demonstrated that TNF alpha, which is produced by keratinocytes, enhances IL-7-induced DETC proliferation, but inhibits IL-2-induced proliferation. The mouse keratinocyte-derived cell line Pam 212 was used to test these cytokines for their capacities to regulate keratinocyte growth. Only gamma IFN, which is produced by DETC, inhibited proliferation in a dose-dependent fashion. These results illustrate three reciprocal pathways by which epidermal cytokines regulate the growth of epidermal cells: 1) a paracrine mechanism by which keratinocyte-derived cytokines (e.g., IL-7 and TNF alpha) promote the growth of DETC, 2) an autocrine mechanism by which DETC-derived cytokines (e.g., IL-2 and IL-4) support their own growth, and 3) a reciprocal pathway in which a cytokine produced by resident epidermal leukocytes (e.g., gamma IFN) modulates the growth of keratinocytes.
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PMID:Reciprocal cytokine-mediated cellular interactions in mouse epidermis: promotion of gamma delta T-cell growth by IL-7 and TNF alpha and inhibition of keratinocyte growth by gamma IFN. 840 21

The aim of this study was to measure the level of cytokines produced by peripheral blood mononuclear cells (PBMNC) in patients with aplastic anemia (AA) and to determine their effect on the clonal growth of normal bone marrow (BM) cells. Twenty-one patients with AA and 11 normal controls were enrolled in this study. Medium conditioned by PBMNC of AA patients in the presence of lipopolysaccharide (LPS) was found to be suppressive to the colony growth of normal BM cells. Thus, we further determined the presence in the PBMNC-conditioned medium (CM) of both inhibitory cytokines: macrophage inflammatory protein-1 alpha (MIP-1 alpha), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta 2 (TGF-beta 2), and interferon-gamma (IFN-gamma), and stimulatory cytokines: interleukin-3 (IL-3) and stem cell factor (SCF). Spontaneous production of MIP-1 alpha was higher in the AA patients than the normal controls (1887 +/- 174 pg/ml vs 1643 +/- 93 pg/ml), but the difference was not significant. After LPS stimulation, the production of MIP-1 alpha was markedly increased in the AA patients, and its level was significantly higher than that of the normal controls (2360 +/- 149 pg/ml vs 1517 +/- 92 pg/ml, p = 0.0022). The level of TNF alpha was also higher in the AA patients. However, IFN-gamma, TGF-beta 2, SCF, and IL-3 were not detectable in the PBMNC-CM of either AA patients or normals. The myelopoietic suppressing effect of AA-PBMNC-CM from each AA patient was significantly blocked by pretreatment with anti-TNF-alpha, resulting in a colony-forming enhancement of 174% +/- 12%. A similar effect was noted in six of 11 AA patients by pretreatment with anti-MIP-1 alpha. We conclude that TNF alpha and MIP-1 alpha can be overproduced by the PBMNC of some AA patients, which may play a role in the progression of AA.
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PMID:Overproduction of inhibitory hematopoietic cytokines by lipopolysaccharide-activated peripheral blood mononuclear cells in patients with aplastic anemia. 853 59

The aim of this study was to measure the level of cytokines produced by peripheral blood mononuclear cells (PBMNC) in patients with aplastic anemia (AA) and determine their effect on normal bone marrow (BM) colony growth. Thirty-five patients with AA and 21 normal controls were enrolled in the study. Medium conditioned by PBMNC of AA patients in the presence of phytohemagglutinin (PHA) was found to be suppressive to the clonal growth of normal BM cells. Thus, we further determined the presence in the PBMNC conditioned medium (CM) of inhibitory cytokines (macrophage inflammatory protein-1 alpha [MIP-1 alpha], transforming growth factor-beta 2 [TGF-beta 2], interferon-gamma [IFN-gamma], and tumor necrosis factor-alpha [TNF-alpha]) and stimulatory cytokines (granulocyte-macrophage colony-stimulatory factor [GM-CSF], interleukin-3 [IL-3], and stem cell factor [SCF]). The results show no significant difference between AA patients and normal controls in the spontaneous production of all cytokines by PBMNC. After PHA stimulation, the production of MIP-1 alpha, IFN-gamma, TNF-alpha, and GM-CSF significantly increased in the cultures of AA patients (p = 0.0009, 0.0002, 0.0022, and 0.0156, respectively). However, both TGF-beta 2 and SCF were undetectable in most of the tested samples. IL-3 was measured in the conditioned medium only after PHA stimulation, but without significant difference between the two groups (p = 0.67). Furthermore, the myelopoietic suppressing effect of AA-PBMNC CM could be significantly blocked by pretreatment with specific antibodies to the corresponding inhibitory cytokines (MIP-1 alpha, IFN-gamma, and TNF-alpha). After antibody neutralization, an apparent change occurred in the clonal growth of normal BM cells incubated with AA-PBMNC CM, resulting in colony enhancement of 205, 131, and 237% by anti-MIP-1 alpha, anti-IFN-gamma, and anti-TNF-alpha, respectively. These results suggest that overproduction of inhibitory cytokines, rather than underproduction of stimulating cytokines, may play a role in the progression of at least some patients with AA.
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PMID:Production of hematopoietic regulatory cytokines by peripheral blood mononuclear cells in patients with aplastic anemia. 853 89


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