Role of trehalose dimycolate-induced interferon-α/β in the restriction of encephalomyocarditis virus growth in vivo and in peritoneal macrophage cultures

Guillemard, Eric; Géniteau-Legendre, M.; Kergot, R; Lemaire, G.; Petit, Jean‐François; Labarre, C; Quero, A.M.

doi:10.1016/0166-3542(95)00047-p

Cited by 8 publications

(7 citation statements)

References 29 publications

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“…This regulatory loop could be beneficial in preventing toxic effects due to an excess of IFN. In this regard, trehalose dimycolate (TDM), a glycolipid from Mycobacterium tuberculosis, injected in mice induces a high level of IFN in PM (15,16), and this production was shown to be also enhanced upon in vitro treatment with inhibitors of NO (data not shown). Of particular interest is the fact that TDMtreated PM are also stimulated to produce substantial level of NO (17), which raises the possibility that NO-mediated negative regulation of IFN pathway occurs even during an inducible high output of NO.…”

Section: Discussionmentioning

confidence: 99%

“…The samples were frozen and thawed once, sonicated for 2 min at 47 kHz in an ultrasonic cleaner (Bransonic B-1200 E1), clarified by centrifugation (1,250 ϫ g, 10 min), and titrated for intra-and extracellular EMCV yields as described above. In parallel, cocultures of L929 cells and PM were performed as a control for cytotoxic activity of PM against uninfected cells and evaluated by a photometric method (16).…”

Section: Methodsmentioning

confidence: 99%

“…Supernatants were removed 24 h later, and VSV was added to each well (80 infectious particles/well). After 48 h the cytopathic effect was evaluated by a photometric method (16). IFN titers were adjusted to a laboratory standard IFN preparation that was calibrated against an international standard for IFN-␤.…”

Section: Methodsmentioning

confidence: 99%

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Inhibitory Activity of Constitutive Nitric Oxide on the Expression of Alpha/Beta Interferon Genes in Murine Peritoneal Macrophages

Guillemard

Varano

Belardelli

et al. 1999

J Virol

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We investigated the role of the constitutive nitric oxide (NO) in the expression of interferon (IFN) genes in mouse peritoneal macrophages (PM). The treatment of PM withl-arginine-N G-amine (AA), a potent inhibitor of NO-producing enzymes, resulted in a marked accumulation of IFN-α4 mRNA and, to a minor extent, of IFN-β mRNA. In contrast, the expression of IFN-γ mRNA, as well as tumor necrosis factor alpha and interleukin-6 mRNA, was not affected. Furthermore, a remarkable increase in the expression of the IFN regulating factor 1 (IRF-1), but not of IRF-2, mRNA was detected in AA-treated PM. To investigate whether the AA-induced activation of the IFN system correlates with the production and antiviral activity of IFN, the extent of encephalomyocarditis virus (EMCV) replication was monitored in AA-treated PM with respect to control cultures. AA treatment strongly inhibited, in a dose-dependent manner, EMCV yields in PM. Likewise, similar results were obtained by the addition of the NO-scavenger carboxyphenyl-tetramethylimidazoline-oxyl-oxide. In addition, inhibition of NO synthesis byN G-mono-methyl-l-arginine in PM strongly decreased virus replication in coculture of PM and EMCV-infected L929 cells, whereas no antiviral effect was observed in L929 cells alone. Moreover, the AA-mediated antiviral activity was abrogated in the presence of antibody to IFN-α/β, whereas antibody to IFN-γ was completely ineffective. Taken together, these results indicate that low levels of NO, constitutively released by resting PM, negatively regulate the expression and activity of IFN-α/β in PM. We suggest that NO acts as a homeostatic agent in the regulation of IFN pathway expression in macrophages.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Inhibitory Activity of Constitutive Nitric Oxide on the Expression of Alpha/Beta Interferon Genes in Murine Peritoneal Macrophages

Guillemard

Varano

Belardelli

et al. 1999

J Virol

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“…TDM has been shown to have a variety of immunostimulatory properties, such as adjuvanticity (40)(41)(42)(43) and enhancement of nonspecific resistance to a number of infectious agents (44)(45)(46)(47)(48)(49). While mechanisms for the toxic effects of TDM have been studied in detail, less is known regarding how TDM stimulates macrophages to become activated.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterial Trehalose Dimycolate Reprograms Macrophage Global Gene Expression and Activates Matrix Metalloproteinases

et al. 2013

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g Trehalose 6,6=-dimycolate (TDM) is a cell wall glycolipid and an important virulence factor of mycobacteria. In order to study the role of TDM in the innate immune response to Mycobacterium tuberculosis, microarray analysis was used to examine gene regulation in murine bone marrow-derived macrophages in response to 90-m-diameter polystyrene microspheres coated with TDM. A large number of genes, particularly those involved in the immune response and macrophage function, were up-or downregulated in response to these TDM-coated beads compared to control beads. Genes involved in the immune response were specifically upregulated in a myeloid differentiation primary response gene 88 (MyD88)-dependent manner. The complexity of the transcriptional response also increased greatly between 2 and 24 h. Matrix metalloproteinases (MMPs) were significantly upregulated at both time points, and this was confirmed by quantitative real-time reverse transcription-PCR (RT-PCR). Using an in vivo Matrigel granuloma model, the presence and activity of MMP-9 were examined by immunohistochemistry and in situ zymography (ISZ), respectively. We found that TDM-coated beads induced MMP-9 expression and activity in Matrigel granulomas. Macrophages were primarily responsible for MMP-9 expression, as granulomas from neutrophil-depleted mice showed staining patterns similar to that for wild-type mice. The relevance of these observations to human disease is supported by the similar induction of MMP-9 in human caseous tuberculosis (TB) granulomas. Given that MMPs likely play an important role in both the construction and breakdown of tuberculous granulomas, our results suggest that TDM may drive MMP expression during TB pathogenesis. Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects approximately one-third of the human population and is the leading bacterial cause of human mortality worldwide, killing 1.45 million individuals per year (1). In the majority of cases, however, the bacteria are sequestered within a well-organized granuloma, where they can remain in a poorly characterized, "latent" state for decades. The granuloma structure is typically composed of centrally located, infected macrophages in various stages of degeneration and necrosis, surrounded by epithelioid macrophages, foamy macrophages, and occasional multinucleated giant cells, all bordered by a mixed population of lymphocytes and a fibrous capsule. This capsule consists of a wall of collagen that is laid down by fibroblasts and must be broken down in order for transmission to occur. Infected individuals who are immunocompetent and/or treated can resolve granulomas, with disaggregation of the accumulated leukocytes, dissolution of the extracellular matrix, and either scar formation or a return to the normal pulmonary architecture. In progressively infected individuals, on the other hand, the granuloma liquefies, the capsule wall cavitates and ruptures into an adjacent airway, and the bacilli multiply and are released (2). While some causes of tubercu...

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“…In early studies induction of nonspecific resistance to intracellular bacteria and activation of macrophages both in terms of parasite phagocytosis and killing was achieved by pretreatment with TOM (34,101). A later publication reported protection of mice against viral infection by TOM-dependent IFN-a and IFN-~pro-duction of macrophages (26). Chemotactic activity of TOM for polymorphonuclear leukocytes and mononuclear cells has been described in the 1970s (62), later studies demonstrated induction of a yet uncharacterized chemotactic factor for macrophages by TOM and glucose monomycolate (GMM) (43,44) and direct chemotactic activity of TOM for macrophages itself (40).…”

Section: Cellular Immune Responsementioning

confidence: 99%

Immunological Properties of Trehalose Dimycolate (Cord Factor) and Other Mycotic Acid‐Containing Glycolipids–‐A Review

Ryll

Kumazawa

Yano

2001

Microbiology and Immunology

142

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Mycolic acids are characteristic fatty acids of Mycobacteria and are responsible for the wax-like consistence of these microorganisms. Decades of research revealed that mycolic acid-containing g1ycolipids, in particular trehalose-6,6'-dimycolate (TDM, cord factor) as their best-studied representative, exert a number of immunomodifying effects. They are able to stimulate innate, early adaptive and both humoral and cellular adaptive immunity. Most functions can be associated with their ability to induce a wide range of chemokines (MCP-t, MIP-ta, IL-8) and cytokines (e.g., IL-12, IFN-y, TNF-a, IL-4, IL-6, IL-tO). This review tries to link well-known properties of mycolic acid-containing glycolipids, e.g., stimulation of cellular and humoral immunity, granuloma formation and anti-tumor activity, with recent findings in molecular immunology and to give an outlook on potential practical applications.

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Role of trehalose dimycolate-induced interferon-α/β in the restriction of encephalomyocarditis virus growth in vivo and in peritoneal macrophage cultures

Cited by 8 publications

References 29 publications

Inhibitory Activity of Constitutive Nitric Oxide on the Expression of Alpha/Beta Interferon Genes in Murine Peritoneal Macrophages

Inhibitory Activity of Constitutive Nitric Oxide on the Expression of Alpha/Beta Interferon Genes in Murine Peritoneal Macrophages

Mycobacterial Trehalose Dimycolate Reprograms Macrophage Global Gene Expression and Activates Matrix Metalloproteinases

Immunological Properties of Trehalose Dimycolate (Cord Factor) and Other Mycotic Acid‐Containing Glycolipids–‐A Review

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