Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026916 (MAC)
 5,226 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Mycobacterium avium complex comprises intracellular bacteria associated with disseminated infection in patients with acquired immune deficiency syndrome (AIDS). Immune defects that lead to infection are unknown but cytokines appear to play an important role in the immunomodulation of host defence mechanisms. We evaluated the cytokine profiles seen temporally after murine M. avium infection. Spleen cells were obtained from M. avium-infected C57BL/6 mice and uninfected mice at weeks 1, 2, 3, 4 and 5. Cells were cultured in vitro and subsequently pulsed with killed M. avium. Supernatants were collected from the cultured splenic cells and the concentrations of interleukin-6 (IL-6), transforming growth factor-beta 1 (TGF-beta 1) and tumour necrosis factor-alpha (TNF-alpha) were measured. TGF-beta 1 was detected at week 1, followed by IL-6 production at week 2. Elevated TNF-alpha levels were observed at week 3. The addition of polyclonal anti-TGF-beta 1 antibody to M. avium-infected peritoneal macrophages in the presence of splenic cell supernatants from weeks 1, 3 and 5 led to decreased bacterial counts compared to controls. Anti-IL-6 antibody did not have any effect on macrophage anti-mycobacterial activity. Concurrently, we observed decreased expression of TNF-alpha receptors on infected macrophages. We propose that the early elevated levels of TGF-beta 1, a known suppressor of macrophage function, in conjunction with down-regulation of TNF-alpha receptors may help explain the suboptimal macrophage response to TNF-alpha, leading to impaired anti-mycobacterial activity.
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PMID:Production of TNF-alpha, IL-6 and TGF-beta, and expression of receptors for TNF-alpha and IL-6, during murine Mycobacterium avium infection. 779 28

The cell line MD-IGF-1, containing an ovine IGF-1 cDNA driven by the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) promoter, was used to study expression of IGF-1 linked to the MMTV-LTR in bovine mammary epithelial cells in response to various hormonal and substratum stimuli. Acute sensitivity of the MMTV-LTR promoter to glucocorticoids and sex steroids was ascertained by transient transfection of parental MAC-T cells with an MMTV-CAT construct. Specifically, CAT activity was induced by glucocorticoids, but not by 17 beta-estradiol or progesterone. Induction of MD-IGF-1 cells with dexamethasone (DEX) alone triggered a 29.5-fold increase in secretion of recombinant IGF-1 (348.9 vs 11.8 pg/micrograms DNA), and stimulated a 1.7-fold increase in total DNA within 72 h. Growth of MD-IGF-1 cells was enhanced by exogenous IGF-1, insulin, and TGF-alpha. In contrast, TGF-beta inhibited cell proliferation, while epidermal growth factor, estrogen, progesterone, and testosterone had no effect. Extracellular matrix from the Engelbreth-Holm-Swarm (EHS) tumor, in the presence of DEX, prolactin (PRL), and insulin stimulated a 29.4-fold increase in secretion of IGF-1 (591.9 pg/microgram DNA), compared with cells in absence of hormones (20.1 pg/micrograms DNA). EHS and DEX plus PRL triggered a 63.2-fold increase in IGF-1 secretion (689.1 pg/micrograms DNA), compared with MD-IGF-1 cells cultured on plastic (10.9 pg/micrograms DNA), in the absence of hormones. These data indicate that the MMTV-LTR is regulated by both lactogenic hormones and extracellular matrix in MD-IGF-1 cells and that the MMTV-LTR may be a useful regulatory element for targeting expression of foreign proteins in bovine mammary epithelial cells.
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PMID:Lactogenic hormones and extracellular matrix regulate expression of IGF-1 linked to MMTV-LTR in mammary epithelial cells. 827 30

Transforming growth factor-beta 1 (TGF-beta 1) selectively modulates hematopoietic cell proliferation. The proliferation of FDC-P1 clone MAC-11, a factor-dependent murine myeloid progenitor cell line, was inhibited differentially by TGF-beta 1: strongly in macrophage colony-stimulating factor (M-CSF), mildly in interleukin-3, and not at all in granulocyte-macrophage-CSF (GM-CSF). Flow cytometry and Western blots showed an unexpected increase in expression of FMS, the receptor for M-CSF, in response to TGF-beta 1. Metabolic labeling with 35S-methionine showed that synthesis of FMS protein accelerated in response to TGF-beta 1, whereas its degradation was unaffected. Northern analyses showed a rapid increase in c-fms RNA after the addition of TGF-beta 1. TGF-beta 1 did not affect kinase activity, cellular phosphotyrosine response, or internalization of FMS. However, TGF-beta 1 inhibited the induction by M-CSF of c-myc RNA analyzed on Northern blots and protein detected by radioimmuno-precipitation. TGF-beta 1 did not affect induction of c-myc expression by GM-CSF or induction of c-fos or c-jun by M-CSF. Therefore, FMS and the GM-CSF receptor induce c-myc via signal transduction pathways that differ in that only the former is inhibited by TGF-beta 1. This inhibition may account for the selective growth regulation by TGF-beta 1.
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PMID:Mechanism of differential inhibition of factor-dependent cell proliferation by transforming growth factor-beta 1: selective uncoupling of FMS from MYC. 849 Jan 68

Although various antimicrobial drugs show appreciable bactericidal activity in the early phase (2 to 4 weeks after infection) of Mycobacterium avium complex (MAC) infections in mice, no drug, as far as we know, can continue to exert the growth inhibiting activity against the bacteria at the site of infection in the progressed stage. Here, we studied the mechanisms of the bacterial regrowth which usually starts around 2-4 weeks after infection. First, the changes in the level of TNF-alpha, IFN-gamma, IL-6 and IL-10 in the lungs and spleen during the course of MAC infections was examined. Tissue levels of TNF-alpha and IL-10 increased around weeks 2 to 4, then rapidly decreased thereafter, and returned to the normal levels by week 8, while levels of IFN-gamma and IL-6 remained very low throughout the observation period. In this experiment, the bacterial CFUs rapidly decreased during the first 2 weeks of the treatment with a rifamycin derivative, KRM-1648, and thereafter the regrowth of the organisms was observed even in mice treated continuously with KRM-1648, although the rate of bacterial growth in the treated mice was much lower than in untreated control mice. Second, effect of either anti-TGF-beta or anti-IL-10 antibody on intracellular growth of MAC in human monocytes cultured in vitro in the medium with or without addition of TNF-alpha or IFN-gamma were examined. Anti-TGF-beta and anti-IL-10 antibodies potently reduced the bacterial growth in monocytes. Effects of TNF-alpha and IFN-gamma in reducing the bacterial growth was potentiated by the addition of either anti-TGF-beta or anti-IL-10 antibody. Third, anti-IL-10 antibody augmented to some extent the chemotherapeutic efficacy of KRM-1648 against MAC infection, when the drug was given to mice at weeks 2 and 4 after infection. From these results, it is suggested that IL-10 derived from MAC-infected macrophages in response to stimulation with some bacterial components, such as lipoarabinomannan, might downregulate the antimicrobial function of host macrophages against MAC.
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PMID:[Mechanism of bacterial regrowth at the sites of infection in Mycobacterium avium complex-infected mice during treatment with chemotherapeutic agents]. 855 14

We previously examined the effects of two Chinese traditional medicines "Mao-Bushi-Saishin-To" (MBST) and "Yokuinin", on the therapeutic efficacies of a benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex (MAC) infection induced in mice. MBST but not Yokuinin potentiated the therapeutic activity of KRM-1648 against MAC infection. In the present study, we examined the effects of these traditional medicines on some M phi cell functions. First, MBST significantly potentiated M phi anti-MAC antimicrobial activity, while Yokuinin did so to a much lesser extent. Secondly, MBST and Yokuinin each strongly inhibited production of nitric oxide (NO) in MAC-infected M phi s. Thirdly, treatment of M phi s with MBST or Yokuinin caused reductions in the accumulation of IL-10 in culture fluids by MAC-infected M phi s during the first 2-days cultivation. On the other hand, in the separate experiment, treatment of M phi s with these drugs caused no significant change in the accumulation of TGF-beta by MAC-infected M phi s at day 7. These findings suggest that these Chinese traditional medicines, particularly MBST, potentiate M phi anti-MAC antimicrobial activity, however, NO do not appear to be crucial effectors in the anti-MAC activity of MBST- or Yokuinin-treated M phi s. Moreover, MBST- and Yokuinin-mediated down-regulation of the production of IL-10 in MAC-infected M phi s may be related to their potentiating effects on M phi anti-MAC activity.
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PMID:[Effects of the Chinese traditional medicines "mao-bushi-saishin-to" and "yokuinin" on the antimycobacterial activity of murine macrophages against Mycobacterium avium complex infection]. 1053 79

Profiles of ICAM-1 expression on cultured murine peritoneal macrophages infected with Mycobacterium avium complex (MAC) were examined, with special reference to modulating roles of TNF-alpha, TGF-beta, and IL-10. When macrophages were infected with MAC, ICAM-1 expression, measured by microscopic counting of ICAM-1+ macrophages stained with anti-ICAM-1 antibody, ELISA, and flow cytometric analysis, was rapidly increased, peaking at day 3 (early-phase up-regulation) due to endogenous TNF-alpha, and thereafter gradually declined to the normal level within 1 week or more (late-phase down-regulation). The late-phase ICAM-1 down-regulation was also seen in macrophages phagocytosing heat-killed MAC and those stimulated with lipopolysaccharide but not in macrophages phagocytosing latex beads. ICAM-1 mRNA expression was augmented markedly at day 1 after MAC infection and thereafter decreased. While TNF-alpha and IL-10 production by MAC-infected macrophages was observed during the first 3 days, TGF-beta production was initiated from day 3 and continued until day 14. Exogenously added TGF-beta strongly inhibited the early-phase increase in ICAM-1 expression by infected macrophages, and the blockade of endogenous TGF-beta with anti-TGF-beta antibody markedly inhibited late-phase ICAM-1 down-regulation. Moderate blocking effect was also observed for anti-IL-10 antibody. On the other hand, late-phase ICAM-1 down-regulation was not prevented by the addition of exogenous TNF-alpha. Therefore, TGF-beta and IL-10, especially the former, appear to play active roles in the late-phase down-regulation of ICAM-1 in MAC-infected macrophages during long-term cultivation.
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PMID:Roles of tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), and IL-10 in the modulation of intercellular adhesion molecule-1 (ICAM-1) expression by macrophages during mycobacterial infection. 1112 38

Studied were made on the profiles of the therapeutic efficacy of KRM-1648 (KRM) against Mycobacterium avium complex (MAC) infection, which was induced in mice at different challenge doses, in reducing bacterial growth in the visceral organs and altering the profiles of cytokine mRNA expression at the sites of infection. First, bacterial growth in the lungs of mice infected with either high or low challenge doses of MAC, was reduced due to KRM treatment. This effect was noted even in the early phase of infection (week 4) in mice, that were given a high-dose infection. Second, marked therapeutic efficacy of KRM was observed in mice, that were given low-dose MAC infection, in terms of the reduction in bacterial loads in the spleen. However, in mice given a high-dose bacterial challenge, KRM did not exhibit such an efficacy. Third, the expression of both proinflammatory cytokines (TNF-alpha, IFN-gamma) and anti-inflammatory cytokines (IL-10, TGF-beta) in mRNA levels were increased at 4 weeks after infection. Notably, all of the cytokines tested for the mRNA expression levels were higher in mice given a low-dose MAC infection as compared to those in mice given a high-dose infection. KRM treatment increased the mRNA levels of these cytokines at week 4, while TGF-beta mRNA expression at week 8 was conversely decreased by KRM treatment. These findings suggest that the profiles of the therapeutic efficacy of KRM vary in mice given low- or high-dose MAC infection.
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PMID:[Profiles of expression of the therapeutic efficacy of KRM-1648 in mice infected with Mycobacterium avium complex at different challenge doses]. 1144 96

The present study was designed to evaluate the distribution of epithelioid cells, myofibroblasts, and TGF-beta1 in the formation of granuloma caused by Mycobacterium avium intracellulare complex (MAC) lung infection. A retrospective study was performed for 9 cases of positive MAC culture in which lung resections were performed between January 1989 and August 1999. Resected lung specimens were evaluated histologically and immunohistochemically for CD68 (stain for monocytes and macrophages, and epithelioid cells) and alpha-smooth muscle actin as well as vimentin (stain for myofibroblasts), and TGF-beta1 was performed. When granuloma was initially formed, no myofibroblasts were found, but as caseous necrosis appeared, the thin epithelioid cell layer was detected and the outer myofibroblast layer gradually became thick. In the cavitary wall, the layer of epithelioid cells and multinucleated giant cells surrounded necrosis, and was associated with the outer layer of myofibroblasts. In addition, the anti-TGF-beta1 antibody stained the cytoplasm of epithelioid cells and multinucleated giant cells, preceding the advent of myofibroblasts. In summary, our present study evaluated distributions of epithelioid cells, myofibroblasts, and TGF-beta along with the morphogenesis of granuloma, and clearly demonstrated the immunohistochemical difference between granuloma with caseous necrosis and granulomas without caseous necrosis.
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PMID:Immunohistochemical distribution of epithelioid cell, myofibroblast, and transforming growth factor-beta1 in the granuloma caused by Mycobacterium avium intracellulare complex pulmonary infection. 1193 80

This study is designed to evaluate radiological, clinical, and pathological findings of Mycobacterium avium complex (MAC) respiratory infection. Two-hundreds of non-tuberculous mycobacteria obtained from upper respiratory tract were collected. Among them, 88 cases were selected according to the strict diagnostic criteria of MAC and chest CT findings were evaluated in 67 cases. In addition, successive chest CT findings were evaluated in 25 cases with MAC respiratory infection. Furthermore, pathological findings were evaluated in 9 surgically-resected lung specimens. Fever, hemoptysis, and dyspnea were more frequently observed in smear-positive patients than in smear-negative, culture-positive patients. Centrilobular nodules and bronchiectasis are frequent observations in patients with MAC. In addition, cavity formation was more frequently observed in smear-positive patients compared with smear negative-cases. Since the score of bronchiectasis in the second CT was significantly higher than in the first CT, progression of bronchiectasis appeared to be caused by MAC infection. Pathologically, extensive granuloma formation throughout the airways was clearly demonstrated. Immunohistochemical staining demonstrated: 1) epithelioid cells and giant cells; and 2) myofibroblasts extensively infiltrating the cavity wall. When granuloma was initially formed, no myofibroblasts were found, but as caseous necrosis appeared, the thin epithelioid cell layer was detected and the outer myofibroblast layer gradually became thick. In the cavitary wall, the layer of epithelioid cells and multinucleated giant cells surrounded necrosis, and was associated with the outer layer of myofibroblasts. In addition, the anti-TGF-beta 1 antibody stained the cytoplasm of epithelioid cells and multinucleated giant cells, preceding the advent of myofibroblasts.
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PMID:[Clinical, radiological, and pathological findings of non-tuberculous mycobacteria respiratory infection]. 1450 27

In order to cope with the worldwide increase in the prevalence of multidrug-resistant tuberculosis and Mycobacterium avium complex (MAC) infections, a number of new antimycobacterial drugs have been or are being synthesized and developed. Development of new protocols for chemotherapy of refractory mycobacterioses is also sharing promise. In this context, one promising strategy is to devise regimens to treat patients with refractory mycobacterioses using ordinary antimycobacterial agents in combination with appropriate immunomodulators. This article deals with the following matters: an outline of the host immune response to mycobacterial pathogens, particularly in terms of mobilization of the cytokine network in response to mycobacterial infection, and adjunctive immunotherapy using (1) recombinant immunomodulating cytokines, (especially Th-1 and Th-1-like cytokines such as IFN-gamma, IL-2, IL-12, IL-18 and GM-CSF), (2) inhibitors of immunosuppressive cytokines (TGF-beta) and some proinflammatory tissue-damaging cytokines (TNF-alpha), and (3) immunomodulatory agents such as ATP and its analogs, imidazoquinoline, diethyldithiocarbamate, poloxamer, dibenzopyran, galactosylceramide, nonsteroidal anti-inflammatory drugs, Chinese traditional medicines, levamisole, synthesized mycobacterial oligoDNA, DNA vaccine expressing mycobacterial HSP65 or IL-12, and heat-killed Mycobacterium vaccae. Although adjunctive immunotherapy is fairly efficacious in treating intractable mycobacterioses, it still features serious problems and dilemmas, such as high cost, occasionally severe side effects, and, in many cases, only modest efficacy in potentiating host defense mechanisms against mycobacterial infections, primarily because of the induction of macrophage-deactivating cytokines during the course of long-term administration of adjunctive agents.
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PMID:Adjunctive immunotherapy of mycobacterial infections. 1554 17


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