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 requirements for activation of anti-mycobacterial and anti-listerial activity of human monocytes were investigated. Human monocytes could be activated to display enhanced anti-mycobacterial activity by a 24-h treatment with lipopolysaccharide. The mediator induced by this treatment was identified as being tumour necrosis factor-alpha (TNF-alpha). Addition of recombinant TNF-alpha (rTNF-alpha) to the cultures of human monocytes for 24 h yielded comparable results (minimal dose required for induction of anti-mycobacterial activity, 10 U ml). Addition of anti-TNF-alpha antibody completely abrogated the effect. A similar treatment protocol failed to activate enhanced anti-listerial activity. To trigger anti-listerial activity, sequential treatment of human monocytes with rTNF-alpha and IL-2 was required. Treatment of monocytes with 10 U ml rTNF-alpha for 24 h followed by incubation in the presence of 200 U/ml of IL-2 for an additional 24 h yielded a reduction of listerial growth which was moderate but statistically significant (P less than 0.001). The activation of monocytes observed with rTNF-alpha/IL-2 treatment was (i) dependent on both cytokines; (ii) sequence dependent (i.e. when IL-2 was added prior to rTNF-alpha, no effect was observed); and (iii) absent in cells treated with one cytokine only. Enhancement of anti-listerial activity by sequential use of cytokines was not accompanied by an increase in oxidative burst, which indicated that oxidative mechanisms were not the reason for the observed Listeria monocytogenes growth restriction. Further support for this hypothesis was obtained after interferon-gamma treatment of human monocytes which led to an augmented PMA-inducible release of active oxygen radicals, but was not paralleled by growth restriction of L. monocytogenes. Our results indicate that TNF-alpha plays a crucial role in the activation of monocytes for growth restriction of intracellular microbes. Activation of human monocytes to restrict the growth of the facultative intracellular bacteria Mycobacterium avium intracellulare and L. monocytogenes, however, follows different patterns, the initial trigger in both cases being provided by TNF-alpha-induced signals.
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PMID:Induction of anti-mycobacterial and anti-listerial activity of human monocytes requires different activation signals. 164 23

The reservoir of Mycobacterium avium complex (MAC) during human infection is the mononuclear phagocyte. In these studies, the ability of certain macrophage-active cytokines to affect MAC growth in human alveolar macrophages was evaluated. Neither recombinant interferon-gamma (2 x 10(2) to 10(3) U/well of 5 x 10(5) cells) nor recombinant macrophage colony-stimulating factor (20 to 50 ng/well), when tested alone, exhibited a consistent ability to induce macrophage targets to inhibit the growth of a clinical strain of MAC serovar 4. However, the combination of these cytokines (1 to 50 ng macrophage colony-stimulating factor + 10(3) U interferon per well) was remarkably effective in diminishing replication of MAC in all experiments. These cytokines were also able to induce alveolar macrophages to restrict MAC growth even though cells were obtained from several individuals with acquired immunodeficiency syndrome (AIDS) or from normal donors and infected in vitro with the human immunodeficiency virus type 1. The effect of this cytokine combination was not abrogated by 10(4) neutralizing U/ml of anti-tumor necrosis factor-alpha antibody. Rather, the combination of interferon-gamma and macrophage colony-stimulating factor appeared to activate intrinsic macrophage mechanisms for restricting MAC growth and deserves further study to determine the potential value of this cytokine combination in the treatment of human infection.
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PMID:Growth inhibition of Mycobacterium avium complex in human alveolar macrophages by the combination of recombinant macrophage colony-stimulating factor and interferon-gamma. 190 Apr 25

Organisms belonging to the Mycobacterium avium complex (MAC) are associated with life-threatening bacteremia in patients with the acquired immunodeficiency syndrome (AIDS). As these organisms survive within macrophages, we examined the ability of recombinant human granulocyte-monocyte colony-stimulating factor (GM-CSF) to activate human monocyte-derived macrophages to inhibit the intracellular growth or kill the most mouse-virulent MAC strain in our collection that belongs to serotype 1. While unstimulated cells did not inhibit intracellular growth of MAC, macrophages activated by GM-CSF (10-10(4) U/ml) inhibited or killed up to 58 +/- 5% of the initial inoculum. This activation was dose-dependent, with maximal change occurring with a dose of 100 U/ml after 72 hr exposure. Inhibition or killing was demonstrated if GM-CSF was given both before or after establishment of infection. The combination of GM-CSF (10(2) U/ml) plus TNF (10(2) U/ml) augmented macrophage killing (range, 31 +/- 4%) compared with GM-CSF (10(2) U/ml) alone, but the combination of recombinant human interferon-gamma (IFN gamma) plus GM-CSF resulted in a significant decrease in intracellular inhibition of growth or killing (13.3 +/- 2%) compared with 57.7 +/- 5% obtained with GM-CSF alone. These results indicate that: 1) GM-CSF can activate macrophages to inhibit intracellular growth or kill MAC; 2) killing may be augmented by TNF; and 3) IFN gamma may impair GM-CSF-dependent macrophage activation.
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PMID:Recombinant granulocyte-macrophage colony-stimulating factor activates human macrophages to inhibit growth or kill Mycobacterium avium complex. 211 63

In order to verify the participation of some cytokines in the expression of the suppressor activity of splenic macrophages (M phi s) induced by Mycobacterium avium complex (MAC) infection, we studied whether anticytokine antibodies were capable of blocking their suppressor activity against concanavalin A (ConA)-induced mitogenesis of splenocytes (SPCs). When either anti-tumor necrosis factor (TNF), anti-transforming growth factor-beta (TGF-beta), or anti-interferon-gamma (IFN-gamma) antibody was added to culture medium, suppressor activity was markedly reduced, in the order of anti-TNF, anti-IFN-gamma, and anti-TGF-beta antibodies. By contrast, neither anti-interleukin-6 (IL-6) nor anti-IL-10 antibody exerted such a blocking effect. Therefore, TNF, IFN-gamma, and TGF-beta seem to be related to the full display of the suppressor function of MAC-induced M phi s. However, TNF-alpha and IFN-gamma but not TGF-beta were substantially lacking in inhibitory action against SPC mitogenesis, when added exogenously. Hence, it is unlikely that TNF-alpha and INF-gamma directly modulated the proliferative response of T cells. On the other hand, both TNF-alpha and IFN-gamma potentiated the effector function of the suppressor M phi s. Because their suppressor activity was severely reduced by NG-monomethyl-L-arginine and aminoguanidine, nitric oxide (NO) synthase inhibitors, an NO-dependent mechanism is important for the expression of the immunosuppressive function of MAC-induced M phi s. Moreover, because these M phi s seem to produce a substantial amount of TNF-alpha in membrane-bound form, cell-to-cell contact might be needed for efficient expression of their suppressor action on target T cells.
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PMID:The role of tumor necrosis factor, interferon-gamma, transforming growth factor-beta, and nitric oxide in the expression of immunosuppressive functions of splenic macrophages induced by Mycobacterium avium complex infection. 749 69

It has recently been shown that human alveolar macrophages can be selectively activated without systemic effect by the use of aerosolized interferon-gamma (IFN gamma), a cytokine that enhances macrophage oxidative and antimicrobial activity. We report the case of a 38-yr-old man negative for human immunodeficiency virus (HIV), with silicosis and advanced cavitary lung disease due to Mycobacterium avium intracellulare (MAI), who failed to improve despite 3 yr of continuous medical therapy with three or more drugs. He received three courses of aerosolized IFN gamma (500 micrograms 3 d per week for 5 wk in two courses and 200 micrograms 3 d a week for 5 wk after a short single trial of subcutaneous IFN gamma). The numbers of MAI decreased in the sputum during therapy, but cultures of the organism remained positive at the same level for the first two treatment periods. The patients sputum became AFB smear negative and the number of colonies decreased significantly after the third course of IFN gamma therapy. Cessation of IFN gamma was associated with a rapid increase in the numbers of MAI in the sputum. Aerosolized IFN gamma can be considered as an adjuvant to conventional drug therapy, with a good tolerance, in cases of lung disease caused by resistant MAI.
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PMID:Aerosolized interferon gamma for Mycobacterium avium-complex lung disease. 766 88

Organisms belonging to the Mycobacterium avium complex (MAC) are common pathogens in immunosuppressed and AIDS patients. This paper reviews the role of cytokines in the pathogenesis of MAC infection. MAC organisms mainly infect monocytes and macrophages, and the effect of HIV infection on susceptibility of macrophages to MAC infection is largely unknown. Both GM-CSF and tumour necrosis factor-alpha can induce mycobacteriostatic/mycobactericidal activity in MAC-infected macrophages. The activity of interferon-gamma on mycobacterial infection appears to be dependent on the type of macrophage: in murine peritoneal and human monocyte-derived macrophages, interferon-gamma does not inhibit the intracellular growth of MAC, whereas in intestinal macrophages interferon-gamma results in inhibition of MAC. Transforming growth factor-beta 1, interleukin-10 and interleukin-6 have all been shown to counteract the immunoactivating cytokines and MAC survival may be due to induction of these inhibitory cytokines within the macrophage. GM-CSF has been given to patients with disseminated MAC infection. Isolated macrophages from these patients demonstrated increased superoxide anion production and enhanced mycobacteriostatic/cidal activity compared with macrophages isolated from the same patients before GM-CSF treatment. These results suggest that GM-CSF may have potential in the treatment of MAC infection.
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PMID:Potential role of cytokines in disseminated mycobacterial infections. 787 49

Since Mycobacterium avium complex (MAC) infects most, if not all, HIV-positive patients, effective regimens for its treatment and prophylaxis are a necessity. We review here the available literature in an attempt to establish clear-cut criteria for the administration of antibiotics and immunotherapy and for the prophylactic treatment of MAC infections. Several antibiotics, chiefly in combination regimens, are active against MAC. Recent data indicate rifabutin as a first-line antibiotic for the treatment of MAC infections. However, since this antibiotic accelerates hepatic metabolism of many drugs (zidovudine in particular), it has the potential to reduce their serum concentrations and hence limit their antiviral activity. Moreover, rifabutin is active against retroviruses only at extremely high concentrations which are not reached in vivo at normally-prescribed dosages. The recent demonstration that the cytokine interferon-gamma (IFN-gamma) in combination with conventional antibiotic therapy may be effective for disseminated MAC infections indicates that immunotherapy could play a pivotal role in the treatment of MAC infections. Lifetime prophylaxis with rifabutin (300 mg/die) is advised for all patients with HIV infection and fewer than 100 CD4 T lymphocytes/mm3 in the peripheral blood: this antibiotic regimen significantly reduces the frequency of disseminated MAC infections. Further studies are required to evaluate the effectiveness of other prophylactic regimens such as azithromycin and clarithromycin. We conclude that rifabutin and immunotherapy with IFN-gamma will play a key role in the treatment of MAC infections.
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PMID:[Treatment and prevention of Mycobacterium avium complex infection in AIDS]. 789 76

We investigated the effects of certain macrophage-active cytokines on the phagocytosis and growth inhibition of Mycobacterium avium complex (MAC) by human alveolar macrophages (AM). We also evaluated the effects of pretreatment with each cytokine on the superoxide anion release (O2-) from AM. The cytokines that we used were recombinant GM-CSF, natural type TNF-alpha, recombinant interferon-gamma (IFN-gamma), and recombinant IL-2. We found that phagocytosis by the various cytokine-stimulated AM was similar to that of unstimulated AM. On the other hand, significant growth inhibition of MAC was observed in the macrophages treated with GM-CSF or TNF-alpha, while no growth inhibition of MAC was observed in the macrophages treated with IFN-gamma or IL-2. Pretreatment with all cytokines tested enhanced the O2- release from AM, but there was no correlation between the enhancement of O2- release and the growth inhibition of MAC. Thus, we concluded that GM-CSF or TNF-alpha could activate AM to inhibit growth of MAC, probably not through the enhanced production of reactive oxygen intermediates.
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PMID:Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) or tumour necrosis factor-alpha (TNF-alpha) activate human alveolar macrophages to inhibit growth of Mycobacterium avium complex. 792 77

Treatment of adult mice with high doses of the immunosuppressive drug cyclophosphamide (CY) induces transient splenic natural suppressor (NS) cell activity mediated largely by cells bearing the MAC-1+ cell-surface marker. Here we show that culture supernatants from mixed lymphocyte reactions (MLR) suppressed by MAC-1+ NS cells exhibit decreased IL-2 and IL-4 activity in bioassays for these lymphokines. However, inhibition of MLR was maximal whether the regulatory cells were added at initiation of culture or 24 hr postinitiation, suggesting that inhibition of lymphokine synthesis is not likely to be the reason for diminished lymphocyte proliferation, since these particular lymphokine genes are known to be transcribed and expressed during the first 12 hr of culture. Furthermore, flow cytofluorometric analysis demonstrated that the presence of MAC-1+ NS cells did not alter the percentage of lymphokine-producing CD4+ T cells in MLR. IL-2 receptor (p55) expression was also normal in suppressed MLR. The addition of exogenous IL-2 and/or IL-4 to MLR failed to reverse the inhibitory effect of MAC-1+ NS cells on lymphocyte proliferation, indicating that these regulatory cells block the utilization of these lymphokines in MLR. The inhibitory effect of MAC-1+ NS cells on lymphocyte proliferation in MLR is dependent on interferon-gamma, since NS activity was dramatically decreased in the presence of neutralizing antibodies to interferon-gamma. MAC-1+ NS cell-induced suppression of MLR was also diminished in the presence of indomethacin, suggesting that prostaglandins play a role in this NS system.
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PMID:The inhibitory effect of cyclophosphamide-induced MAC-1+ natural suppressor cells on IL-2 and IL-4 utilization in MLR. 797 16

In the 1980s, substantive experimental data and emerging clinical results suggested that interferon-gamma (IFN-gamma), a T-cell-derived lymphokine with broad macrophage-activating effects, had considerable potential in the treatment of nonviral infections as a host defense-enhancing antimicrobial agent. During the past 6 years, the breadth of the experimental activity with IFN-gamma against nonviral pathogens has been expanded still further, and pilot studies and formal clinical trials using IFN-gamma have been undertaken in the treatment of patients both at risk for and with active infections. Thus far, IFN-gamma has been approved for use as prophylaxis in patients with chronic granulomatous disease. However, IFN-gamma also appears effective as adjunctive therapy for at least one disseminated intracellular infection (visceral leishmaniasis), and in conjunction with conventional therapy, may benefit patients with certain forms of cutaneous leishmaniasis, disseminated Mycobacterium avium complex infection, and lepromatous leprosy. Despite a rationale for its use, IFN-gamma has not yet been tested in tuberculosis or fungal or common bacterial infections nor sufficiently examined in the prevention and/or treatment of the opportunistic infections related to acquired immunodeficiency syndrome. IFN-gamma remains a promising host defense-enhancing cytokine with still unexplored clinical potential.
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PMID:Interferon-gamma and host antimicrobial defense: current and future clinical applications. 797 35


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