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Query: UMLS:C0026918 (Mycobacterium)
 52,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine bone marrow-derived macrophages (BMM) are able to inhibit the intracellular growth of Mycobacterium bovis and Mycobacterium tuberculosis H37Rv after activation with recombinant (r) IFN and growth inhibition is mediated by reactive nitrogen intermediates (RNI) derived from L-arginine. We now demonstrate that tumor necrosis factor (TNF)-alpha acts as an endogenous cofactor in the induction of mycobacterial growth inhibition. TNF-alpha was produced by BMM stimulated with rIFN-gamma and infected with mycobacteria, and a specific antiserum to TNF-alpha inhibited rIFN-gamma-induced production of RNI as well as growth inhibition of M. bovis. IL-10, a cytokine which suppresses antimycobacterial macrophage functions, was also produced by BMM activated with rIFN-gamma and infected with M. bovis. IFN-gamma-induced production of TNF-alpha and of reactive nitrogen intermediates as well as mycobacterial growth inhibition were inhibited by exogenous IL-10, but only when given prior to IFN-gamma stimulation. We conclude that the outcome of mycobacterial infection is regulated by a coordinate interplay between IFN-gamma, TNF-alpha and IL-10.
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PMID:Growth inhibition of Mycobacterium bovis by IFN-gamma stimulated macrophages: regulation by endogenous tumor necrosis factor-alpha and by IL-10. 808 Aug 40

Specific cytotoxic T cells against intracellular pathogens may be generated in vitro. On the other hand it is well known that cytokines can regulate almost every aspect of immune function. The aim of this study was to evaluate the effect of some cytokines on the generation of cytotoxic T cells with specificity for Mycobacterium leprae- or PPD-pulsed autologous macrophages from leprosy patients and normal controls. Peripheral blood mononuclear cells from M. bovis BCG-immunized controls or from leprosy patients were stimulated with antigen, in the presence or absence of cytokines, for 7 days. These were used as effector cells in a 4-h [51Cr]-release assay. Our results show that development of cytotoxic T cells may be enhanced by gamma-IFN, IL-6 or the combination of IL-6 and IL-2. Addition of IL-2 or TNF-alpha alone did not modify the generation of cytotoxic activity. IL-4 down-regulated the cytotoxic response and gamma-IFN was able to counteract this effect. Hence, the generation of specific cytotoxic T cells can be modulated by cytokines. Whether this cytotoxic mechanism contributes to protection or tissue damage in M. leprae infection remains to be determined.
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PMID:IFN-gamma, IL-6 and IL-4 modulate M. leprae- or PPD-specific cytotoxic T cells in leprosy patients. 825 14

The relative phagocytosis and intracellular fate of Mycobacterium tuberculosis (MTB) (H37Ra) in human alveolar macrophages (AM) and their precursors blood monocytes (MN) was investigated. Uptake of MTB by MN and AM was confirmed by electron microscopy. At an infection ratio of 100:1 (MTB:target cell), the percentage of infected AM and the number of MTB per AM was > MN (p < 0.001, p < 0.0001, respectively). Uptake of MTB was increased by increasing concentrations of serum and decreased in the presence of heat-inactivated serum. Among complement receptors (CR) CR1, CR3, and CR4, the major CR mediating uptake of MTB by MN were CR1 and CR3, whereas for AM, CR4 was the major CR. When MN and AM were infected with MTB and cultured for up to 7 days, AM limited intracellular growth of MTB more effectively than MN as determined by a CFU assay. MTB stimulated production of TNF-alpha by mononuclear phagocytes and by AM > MN (p < 0.007). Pentoxifylline inhibited TNF-alpha production by mononuclear phagocytes and concurrently increased MTB growth (AM > MN). A polyclonal neutralizing antibody to TNF-alpha also increased MTB growth in AM. Thus, AM are more efficient in phagocytosis of MTB than MN, and uptake is mediated through CR4 to a greater extent than CR1 or CR3. The slowed replication of MTB in AM is associated with an increase in TNF-alpha production, and intracellular growth is promoted by pentoxifylline and neutralizing antibody to TNF-alpha. These data suggest that AM may play a prominent and efficient role in the primary defense of the lung in tuberculosis through CR-mediated uptake, predominantly CR4, and TNF-alpha-mediated killing of MTB.
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PMID:Complement receptor-mediated uptake and tumor necrosis factor-alpha-mediated growth inhibition of Mycobacterium tuberculosis by human alveolar macrophages. 828 49

The effects of a concurrent HIV-1 and Mycobacterium avium infection in vitro were assessed in human peripheral blood-derived macrophages (M phi). M phi were infected with HIV-1Ba-L strain for 14 days then infected with M. avium (HIV/M. avium) or treated with LPS (HIV/LPS). At various times after M. avium or LPS treatment, Mo phi cultures were harvested for quantitation of HIV and M. avium replication, as well as M phi cellular viability. In addition, mRNA and supernatants were collected for assessment of induction of the cytokines TNF-alpha, IL-1 beta and IL-6. M. avium multiplication was greater in HIV-infected M phi, whereas no difference in virus production, based on p24 and RT values, was observed between HIV-infected cells and HIV/M. avium or HIV/LPS M phi. M. avium infection of HIV-1-infected M phi also caused a decrease in viability of the M phi. HIV-1/M. avium-infected M phi had a 24 h delay in induction of TNF-alpha steady state mRNA when compared with HIV/LPS or M. avium only or LPS-only treated M phi. HIV infection also increased the amount and the length of induction of IL-1 beta and IL-6 steady state mRNA stimulated by either M. avium or LPS. In addition, prolonged and increased protein production of TNF-alpha, IL-6, and IL-1 beta was observed in HIV/M. avium-infected cells when compared with the other treatments. In direct contrast to M. avium infection, no significant differences in LPS-induced protein production of the three cytokines was observed between HIV-1-infected and -noninfected M phi. Treatment of HIV/M. avium-infected cells with human rGM-CSF did not increase either the time or quantity of induction of TNF-alpha mRNA or protein production in HIV/M. avium-infected M phi. The increase in M. avium numbers, dysregulation of cytokine production, and subsequent cell death seen in vitro in HIV/M. avium-infected human M phi may reflect part of the underlying cause of the highly disseminated M. avium disease pattern observed in AIDS patients.
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PMID:Concurrent infection of human macrophages with HIV-1 and Mycobacterium avium results in decreased cell viability, increased M. avium multiplication and altered cytokine production. 834 8

Transforming growth factor-beta 1 (TGF-beta 1) is a potent immunoregulatory molecule. It modulates production of cytokines, such as TNF-alpha and IL-6, and cell response to cytokine stimulation. Mycobacterium avium is an intracellular bacterium that multiplies within macrophages. The reason why M. avium can survive within macrophages is still unknown but probably is multifactorial. Exposure of M. avium-infected macrophages to rTGF-beta 1 before TNF stimulation significantly decreases the mycobactericidal/mycobacteriostatic activity associated with treatment with TNF. Infection of human monocyte-derived macrophages in vitro with M. avium strains belonging to serovars 1, 4, and 8 induced secretion of biologically active TGF-beta. The production of TGF-beta was strain dependent and was more pronounced in macrophages infected with virulent strains. Incubation of macrophages with M. avium-derived 33-kDa and 65-kDa proteins was associated with significant release of biologically active TGF-beta. Treatment of M. avium-infected macrophages with rTNF-alpha in the presence of anti-TGF-beta 1 antibody induced significantly greater killing of M. avium than did treatment of macrophages with TNF-alpha in the absence of anti-TGF-beta 1 antibody. In addition, macrophage monolayers treated with anti-TGF-beta 1 antibody before infection with M. avium showed mycobactericidal activity after stimulation with rIFN-gamma; in contrast, no effect of IFN-gamma was seen in monolayers not treated with anti-TGF-beta 1 antibody. We conclude that TGF-beta 1 produced after M. avium infection is a potent inhibitor of macrophage activation by cytokines. This inhibition may have an important role in the regulation of the immune response against M. avium.
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PMID:Production of transforming growth factor-beta by Mycobacterium avium-infected human macrophages is associated with unresponsiveness to IFN-gamma. 843 19

Lipoarabinomannan (LAM) is a major cell-wall associated glycolipid produced by Mycobacterium tuberculosis and Mycobacterium leprae. Previous work demonstrated that LAM from avirulent (H37Ra) and virulent (Erdman) strains of M. tuberculosis differ in structure at their non-reducing termini. In this study the effects of the H37Ra and Erdman LAM on the activation of murine bone marrow-derived macrophages has been investigated. Their abilities to elicit immediate early gene responses at mRNA (c-fos, JE, KC) and protein (TNF-alpha secretion) levels, and nitrite production, was examined. H37Ra LAM, but not Erdman LAM, elicited TNF-alpha secretion at 1000 ng/ml. Neither stimulated production of reactive nitrogen intermediates (RNI). Addition of 25 U/ml IFN-gamma enhanced TNF-alpha secretion in response to H37Ra LAM, reducing the threshold level of LAM required to 10 to 100 ng/ml. In contrast, Erdman LAM at concentrations up to 1000 ng/ml could not induce macrophage TNF-alpha secretion even in the presence of 25 U/ml IFN-gamma. H37Ra LAM also synergized with IFN-gamma to stimulate enhanced production of RNI, whereas IFN-gamma and Erdman LAM did not elicit RNI production. Examination of events before TNF-alpha and RNI production revealed that H37Ra LAM, like LPS, was able to induce increased levels of mRNA expression for c-fos, KC, and JE, with similar kinetics but reduced potency compared with LPS. Erdman LAM in concentrations up to 2500 ng/ml was unable to stimulate c-fos, KC, or JE expression. IFN-gamma at 25 U/ml was itself a potent stimulus of JE expression, and synergized with 1000 ng/ml H37Ra, and to a lesser extent, Erdman LAM for the induction of JE. In contrast, IFN-gamma inhibited H37Ra LAM stimulation of KC expression. The phenomenon of avoiding the stimulation of macrophage immediate early gene expression may be an important determinant of mycobacterial virulence.
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PMID:Macrophage activation: lipoarabinomannan from avirulent and virulent strains of Mycobacterium tuberculosis differentially induces the early genes c-fos, KC, JE, and tumor necrosis factor-alpha. 843 23

Human monocyte-derived macrophages (M phi) from the majority of normal donors respond to inoculation with Mycobacterium avium, serotype 4, (MAI) by elaboration of the inflammatory monokines TNF-alpha, IL-1 beta, and IL-6, which are of central importance for the protection against bacterial and parasitic infections. Peak TNF-alpha mRNA levels were of brief duration, being maximal at 1.5 h, and were only slightly higher than background levels at 4 h. Increases of IL-1 beta and IL-6 mRNA levels, on the other hand, persisted for 48 to 72 h. In contrast to LPS, MAI induced the production of only small amounts of TNF-alpha protein in the first 12 h and of large amounts of IL-1 beta and IL-6 protein between 3 and 72 h. MAI-induced TNF-alpha transcripts, in contrast to LPS induced TNF-alpha transcripts, were highly unstable. Their accumulation was blocked and their t 1/2 significantly decreased by the protein kinase C inhibitor staurosporine. In contrast, LPS-induced increases of TNF-alpha mRNA levels and MAI-induced increases of IL-1 beta and IL-6 mRNA levels were PKC independent. The cAMP- and cGMP-dependent protein kinase inhibitors, KT5720 and KT5823, respectively, and the tyrosine kinase inhibitors herbimycin and erbstatin had no effect on the MAI-dependent mRNA accumulation of TNF-alpha, IL-1 beta, and IL-6. W7, a calmodulin-dependent protein kinase inhibitor, was inhibitory in all cases. Thus, MAI-induced TNF-alpha mRNA accumulation is of short duration and PKC dependent. MAI-induced TNF-alpha protein production is low, possibly resulting in a mitigated antimicrobial effect.
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PMID:TNF-alpha response of human monocyte-derived macrophages to Mycobacterium avium, serovar 4, is of brief duration and protein kinase C dependent. 845 62

Mycobacterium avium is an intracellular pathogen that causes disseminated infection in patients with AIDS. Colonial morphotype (smooth-transparent (SmT) vs smooth-domed (SmD)) is a key determinant of virulence in mice and the capacity for replication in human monocytes. Some cytokines (IL-1 and IL-6) promote, whereas others (IFN-gamma and TNF) inhibit intracellular M. avium growth. The specific factors that determine virulence of M. avium, however, are not clear. In this study, we examined cytokine expression by human monocytes stimulated with isogeneic cloned isolates of M. avium. Monocytes were prepared from healthy donors and cultured with or without isogeneic M. avium for up to 7 days. Cytokine levels (IL-1, IL-6, and TNF-alpha) in monocyte supernatants and cell lysates were measured by immunoassay using an ELISA. The expression of cytokine mRNA by monocytes infected with M. avium also was determined by extracting total RNA and subjecting it to Northern blot analysis. Optimal cytokine release occurred at 24 h. SmD induced higher levels of the following cytokines in supernatants than SmT: IL-1 alpha (140 +/- 32 (mean +/- SE) vs 47 +/- 16 pg/ml, p < 0.02), IL-1 beta (4.0 +/- 0.9 vs 1.7 +/- 0.5 ng/ml, p < 0.01), and TNF-alpha (2725 +/- 546 vs 1464 +/- 409 pg/ml, p < 0.01). IL-6 production was comparable for both strains. SmD and SmT isolates induced comparable levels of steady state mRNA for IL-1 beta, TNF, and IL-6. Pulse-chase analysis indicated that differences in cytokine expression between SmT and SmD occurred in monocyte lysates at the earliest time point (immediately after pulse-labeling). The dissociation of the expression of specific mRNA from production of IL-1 and TNF suggests that translational capacity for the expression of certain cytokines was reduced by the more virulent SmT. Differential induction of cytokine may be a factor in the pathogenicity of M. avium strains isolated from patients with AIDS.
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PMID:Colonial morphotype as a determinant of cytokine expression by human monocytes infected with Mycobacterium avium. 845 66

Recent analyses of antimycobacterial T cells clones from a small number of individuals indicate that mycobacteria preferentially induce Th cells that produce high levels of IFN-gamma and no or little IL-4 in Mycobacterium leprae-resistant tuberculoid leprosy (TT) patients and healthy subjects, whereas in one study M. leprae-induced Ts clones from polar lepromatous leprosy (LL) patients showed a reciprocal cytokine secretion profile and mediated their suppressive activity via the release of high levels of IL-4. We have evaluated these findings in peripheral blood T cells from a larger panel of TT and LL patients as well as healthy individuals. Mycobacterium-reactive T cell lines generated from the PBMC of these individuals were tested for cytokine secretion and proliferative capacity in response to M. leprae, Mycobacterium tuberculosis, and various individual mycobacterial Ag. The lepromatous pole of the leprosy spectrum was additionally investigated by analyzing the cytokine-secretion profile of M. leprae-induced (suppressor) T cell clones as well as primary ex vivo PBMC. All T cell lines from healthy individuals and TT patients responding to M. leprae, M. tuberculosis, or individual Ag, produced high levels of IFN-gamma and TNF-alpha but little or no IL-4 and IL-6. At the lepromatous pole, T cell lines failed to proliferate upon stimulation with M. leprae but in some cases produced significant levels of IFN-gamma. No IL-4 or IL-6 secretion was observed in response to M. leprae. These lines displayed strong proliferation and Th1-like cytokine production upon stimulation with M. tuberculosis. Similarly, stimulation of primary PBMC from LL patients with M. leprae or M. tuberculosis resulted in the release of IFN-gamma but no detectable IL-4 production. Control tetanus toxoid-reactive T cell lines from the same individuals instead produced large amounts of IL-4 and low levels of IFN-gamma. The analysis of M. leprae-induced T cell clones, including those with known suppressive activity, revealed that all lepromatous T cell clones produced large amounts of IFN-gamma. Most of these clones released no or little IL-4, but some clones produced higher levels of IL-4 in addition to IFN-gamma. Most clones tested produced IL-10 as well. The suppressor activity of suppressor T cell clones could not be inhibited by a neutralizing anti-IL-4 antibody and only in one case by neutralizing anti-IL-10 antibody. Anti-IL-4 and anti-IL-10 could not overcome the M. leprae-specific unresponsiveness observed in primary PBMC from LL patients.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Analysis of cytokine production by Mycobacterium-reactive T cells. Failure to explain Mycobacterium leprae-specific nonresponsiveness of peripheral blood T cells from lepromatous leprosy patients. 848 51

IL-10 and IL-4 have been shown to exert an inhibitory effect on cell-mediated immune responses. Our previous studies of leprosy demonstrated that IL-10 and IL-4 mRNA were preferentially expressed in lesions from lepromatous patients, those immunologically unresponsive individuals that manifest widespread infection. To define more precisely the regulatory roles of these two cytokines in the immune response to infection, we studied in vitro responses to Mycobacterium leprae. M. leprae triggered IL-10 release from PBMC of patients and healthy donors; the predominant source of the IL-10 was found to be monocytes/macrophages. Stimulation of PBMC in the presence of neutralizing anti-IL-10 mAb indicated that endogenous IL-10 production inhibits PBMC proliferation and release of TNF-alpha, GM-CSF, and IFN-gamma. Paradoxically, studies using neutralizing anti-IL-4 mAb indicated that endogenous IL-4 production enhances PBMC proliferative responses most strikingly in lepromatous patients. We found that rIL-4 expanded CD8+ T cells from lepromatous patients in vitro. CD8+ T cells from lepromatous patients have been shown to suppress CD4+ T cell responses, in part by the release of IL-4. Our study indicated that endogenous IL-4 production inhibited IL-10 secretion and, concomitantly, increased TNF-alpha and GM-CSF release. The present data suggest that, on balance, IL-4 and IL-10 contribute to immunosuppression in human infectious disease.
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PMID:Immunosuppressive roles for IL-10 and IL-4 in human infection. In vitro modulation of T cell responses in leprosy. 851 73


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