Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026918 (Mycobacterium)
 52,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Downstream signal transduction via heterotrimeric GTP-binding proteins to protein kinase C has been reported to be a central event in induction of rapid phagocytosis of extracellular particles by macrophages. However, the signalling pathway involved in mycobacterial uptake and phagosome biogenesis is poorly understood, and there is lack of information about in situ localization of PKC, cytoskeletal proteins, and G-proteins in mycobacterial vacuoles. Employing immunocytochemical methods, we provide evidence that alpha-subunits of stimulatory and inhibitory G-proteins and PKC beta as well as two major cytoskeletal components, microfilaments and microtubules, participate in uptake of Mycobacterium bovis BCG by human macrophages and co-localize in phagosomes. This implies that cellular signalling via G-proteins and PKC beta may occur not only at the level of the plasma membrane; rather, the alpha-subunit of G-proteins and PKC beta may be translocated to the effector proteins involved in phagosomal biogenesis. A similar pattern of accumulation of G-proteins, PKC, and both microfilamental and microtubular cytoskeleton around vacuoles containing internalized latex beads indicates their general role in phagocytosis.
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PMID:Signal transduction and phagosome biogenesis in human macrophages during phagocytosis of Mycobacterium bovis BCG. 915 Jul 98

A soluble Ca2+/calmodulin dependent protein kinase has been partially purified (approximately 400 fold) from Mycobacterium smegmatis ATCC 607 using several purification steps like ammonium sulphate precipitation (30-60%), Sepharose CL-6B gel filtration, DEAE-cellulose and finally calmodulin-agarose affinity chromatography. On SDS-PAGE, this enzyme preparation showed a major protein band of molecular mass 35 kD and its activity was dependent on calcium, calmodulin and ATP when measured under saturating histone IIs (exogenous substrate) concentration. Phosphorylation of histone IIs was inhibited by W-7 (calmodulin inhibitor) and KN-62 (CaM-kinase inhibitor) with IC50 of 1.5 and 0.25 microm respectively, but was not affected by inhibitors of PKA (Sigma P5015) and PKC (H-7). All these results confirm that purified enzyme is Ca2+/calmodulin dependent protein kinase of M. smegmatis. The protein kinase of M. smegmatis demonstrated a narrow substrate specificity for both exogenous as well as endogenous substrates. These results suggest that purified CaM-kinase must be involved in regulating specific function(s) in this organism.
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PMID:Ca2+/calmodulin dependent protein kinase from Mycobacterium smegmatis ATCC 607. 965 95

Previously, we have found that immunosuppressive macrophages (M(phi)s) induced by Mycobacterium intracellulare-infection (MI-M(phi)s) required cell contact with target T cells to express their suppressor activity against concanavalin A (Con A)-induced T cell mitogenesis. In this study, we examined the profiles of cell-to-cell interaction of MI-M(phi)s with target T cells. First, MI-M(phi)s displayed suppressor activity in an H-2 allele-unrestricted manner, indicating that MHC molecules are not required for cell contact. The suppressor activity of MI-M(phi)s was reduced markedly by paraformaldehyde fixation or treatment with cytochalasin B or colchicine, indicating that vital membrane functions are required for their suppressor activity. Secondly, the suppressor activity of MI-M(phi)s was independent of cell-to-cell interaction via CD40 ligand/CD40 and M(phi)-derived indoleamine 2,3-dioxygenase, which causes rapid degradation of tryptophan in T cells. Thirdly, precultivation of splenocytes with MI-M(phi)s, allowing cell-to-cell contact, reduced Con A- or anti-CD3 antibody-induced mitogenesis but not phorbol myristate acetate/calcium ionophore A23187-elicited proliferation of T cells. In addition, co-cultivation of T cells with MI-M(phi)s caused marked changes in profiles of the tyrosine phosphorylation of 33 kDa, 34 kDa and 35-kDa proteins and, moreover, the activation of protein kinase C and its translocation to the cell membrane. It thus appears that suppressor signals of MI-M(phi)s, which are transmitted to the target T cells via cell contact, principally cross-talk with the early signalling events before the activation of PKC and/or intracellular calcium mobilization.
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PMID:Profiles of cell-to-cell interaction of Mycobacterium intracellulare-induced immunosuppressive macrophages with target T cells in terms of suppressor signal transmission. 1216 83

Nramp1 (natural resistance-associated macrophage protein 1) is a phagosomal iron transport molecule. In addition to its anti-microbial activity, Nramp1 exerts a wide range of pleiotropic effects, including increased stability of Nramp1 mRNA and a variety of other mRNA species. Previously, we showed that the increased stability of Nramp1 mRNA is regulated by an oxidant-generated signaling pathway that requires PKC. In the current study, we show that inhibition of ERK1,2 and p38 MAP kinase activities decreases Nramp1 mRNA stability in Mycobacterium avium infected RAW264.7 cells expressing Nramp1(Gly169) but not in RAW264.7-Nramp1(Asp169) cells. Phosphorylation of ERK1,2 and p38 MAP kinases, which could be inhibited by the anti-oxidant BHA and a protein kinase C inhibitor, was higher in M. avium infected RAW264.7-Nramp1(Gly169) cells than in RAW26.47-Nramp1(Asp169) cells. These results suggest that generation of oxidants by Nramp1 iron transport activates MAP kinase signaling cascades that result in stabilization of Nramp1 mRNA.
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PMID:Role of MAP kinase activation in Nramp1 mRNA stability in RAW264.7 macrophages expressing Nramp1(Gly169). 1220 56

Previous studies have shown that the ability of Mycobacterium tuberculosis to block a Ca(2+) flux is an important step in its capacity to halt phagosome maturation. This affect on Ca(2+) release results from M. tuberculosis inhibition of sphingosine kinase (SPK) activity. However, these studies did not address the potential role of SPK and Ca(2+) in other aspects of macrophage activation including production of proinflammatory mediators. We previously showed that nonpathogenic Mycobacterium smegmatis and to a lesser extent pathogenic Mycobacterium avium, activate Ca(2+)-dependent calmodulin/calmodulin kinase and MAPK pathways in murine macrophages leading to TNF-alpha production. However, whether SPK functions in promoting MAPK activation upon mycobacterial infection was not defined in these studies. In the present work we found that SPK is required for ERK1/2 activation in murine macrophages infected with either M. avium or M. smegmatis. Phosphoinositide-specific phospholipase C (PI-PLC) and conventional protein kinase C (cPKC) were also important for ERK1/2 activation. Moreover, there was increased activation of cPKC and PI3K in macrophages infected with M. smegmatis compared with M. avium. This cPKC and PI3K activation was dependent on SPK and PI-PLC. Finally, in macrophages infected with M. smegmatis compared with M. avium, we observed enhanced secretion of TNF-alpha, IL-6, RANTES, and G-CSF and found production of these inflammatory mediators to be dependent on SPK, PI-PLC, cPKC, and PI3K. These studies are the first to show that the macrophage proinflammatory response following a mycobacterial infection is regulated by SPK/PI-PLC/PKC activation of ERK1/2 and PI3K pathways.
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PMID:Macrophage's proinflammatory response to a mycobacterial infection is dependent on sphingosine kinase-mediated activation of phosphatidylinositol phospholipase C, protein kinase C, ERK1/2, and phosphatidylinositol 3-kinase. 1662 18

Complement C5-deficient (C5(-/-)) macrophages derived from B.10 congenic mice were found to be defective in killing intracellular Mycobacterium tuberculosis (MTB). They were bacteriostatic after activation with IFN-gamma alone but bactericidal in the combined presence of IFN-gamma and C5-derived C5a anaphylatoxin that was deficient among these macrophages. Reduced killing correlated with a decreased production of reactive oxygen species (ROS) in the C5(-/-) macrophages measured using fluorescent probes. Furthermore, a lack of colocalization of p47(phox) protein of the NADPH oxidase (phox) complex with GFP-expressing MTB (gfpMTB) indicated a defective assembly of the phox complex on phagosomes. Reconstitution with C5a, a known ROS activator, enhanced the assembly of phox complex on the phagosomes as well as the production of ROS that inhibited the growth of MTB. Protein kinase C (PKC) isoforms are involved in the phosphorylation and translocation of p47(phox) onto bacterial phagosomes. Western blot analysis demonstrated a defective phosphorylation of PKC (alpha, beta, delta) and PKC-zeta in the cytosol of C5(-/-) macrophages compared with C5 intact (C5(+/+)) macrophages. Furthermore, in situ fluorescent labeling of phagosomes indicated that PKC-beta and PKC-zeta were the isoforms that are not phosphorylated in C5(-/-) macrophages. Because Fc receptor-mediated phox assembly was normal in both C5(-/-) and C5(+/+) macrophages, the defect in phox assembly around MTB phagosomes was specific to C5 deficiency. Reduced bactericidal function of C5(-/-) macrophages thus appears to be due to a defective assembly and production of ROS that prevents effective killing of intracellular MTB.
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PMID:The reduced bactericidal function of complement C5-deficient murine macrophages is associated with defects in the synthesis and delivery of reactive oxygen radicals to mycobacterial phagosomes. 1698 8

Mycobacterium leprae, the causative agent of leprosy, challenges host defense mechanism by impairing the signal transduction of T cells which leads to downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production. In this study we sought to identify how soluble forms of M. leprae antigen(s) or particulate (liposome) delivery of the same antigens with two immunomodulators Murabutide and T cell peptide of Trat protein influence the transcription of IL-2 gene in anergic T cells of lepromatous patients. It was demonstrated that MLCwA/ManLAM stimulated cells of BL/LL patients showed defects in both jun-NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activities there by resulting in decreased AP-1 activity. Additionally these cells showed reduced calcium levels, PKC activity and calcineurin (CN) activity. This led to impaired nuclear translocation of NFkappaB and NFAT in these patients. In contrast, when same M. leprae antigen(s) were incorporated with the two immunomodulators in liposomal form, increased transcription of IL-2 gene was observed especially in BL/LL patients which appears to be due to, at least in part, to increased expression of AP-1 Fos and Jun family members, NFkappaB and NFAT1 proteins. The increased expression of these transcription factors correlated with increased ERK/JNK, PKC and CN activities in these patients. Since activation of ERK/JNK/PKC kinases and CN phosphatase are required for stimulation of IL-2 transcription, these data provide a molecular explanation for the block in IL-2 production by M. leprae antigens. Thus the above study revealed suppression of all the three distinct biochemical pathways, viz. Ca-CN-NFAT pathway, PKC-NF-kappaB pathway, and MAPK-AP-1 pathway by M. leprae antigen(s) in anergized T cells of lepromatous patients which were activated by liposomal delivery of M. leprae antigens containing the two immunomodulators leading to optimal induction of IL-2 gene expression, which was required for the activation, and proliferation of T cells in lepromatous patients.
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PMID:Alterations in T cell signal transduction by M. leprae antigens is associated with downregulation of second messengers PKC, calcium, calcineurin, MAPK and various transcription factors in leprosy patients. 1704 60

Given the fact that Mycobacterium tuberculosis (Mtb) may respond to the intracellular milieu of the macrophage with the induction of environmentally regulated genes required for survival and growth of the bacteria we assumed that the protein kinases may also be the factors in Mycobacterium-macrophage interaction. Since, protein kinases play a major role in various critical cellular processes including regulation of immune responses, we describe the fate of expression and phosphorylation of protein kinase C in macrophage cell lines exposed to Mtb H37Rv and raised the question whether the change in the events of expression and phosphorylation are the results of direct interaction of bacilli with macrophages and/or, are also indirectly mediated by specific cytokines that are induced in response to exposure. Our results show that only novel PKCs are phosphorylated during infection of macrophages by pathogenic and non-pathogenic mycobacteria and the alteration is a result of direct host-bacilli association which is independent of cytokines as mediators. Expression of PKC-alpha (conventional PKC isoform) was down regulated by Mtb H37Rv. In contrast the non-pathogenic fast grower Mycobacterium smegmatis (MS) increased the expression and phosphorylation of PKC-alpha. PKC-alpha was also increased in macrophages treated with serum of mice immunized with Mtb H37Rv. The study has shown that pathogenic and non-pathogenic mycobacteria categorically select the type of protein kinases C for activation/deactivation.
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PMID:Differential regulation of protein kinase C isoforms of macrophages by pathogenic and non-pathogenic mycobacteria. 1864 46

Mycobacterium indicus pranii (MIP), also known as Mw, is a saprophytic, non-pathogenic strain of Mycobacterium and is commercially available as a heat-killed vaccine for leprosy and recently tuberculosis (TB) as part of MDT. In this study we provide evidence that cell-free supernatant collected from original MIP suspension induces rapid and enhanced apoptosis in mouse peritoneal macrophages in vitro. It is demonstrated that the MIP cell-free supernatant induced apoptosis is mitochondria-mediated and caspase independent and involves mitochondrial translocation of Bax and subsequent release of AIF and cytochrome c from the mitochondria. Experiments with pharmacological inhibitors suggest a possible role of PKC in mitochondria-mediated apoptosis of macrophages.
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PMID:Mycobacterium indicus pranii supernatant induces apoptotic cell death in mouse peritoneal macrophages in vitro. 2134 4


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