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Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death.

ABSTRACT: Tumor necrosis factor (TNF), a key effector in controlling tuberculosis, is thought to exert protection by directing formation of granulomas, organized aggregates of macrophages and other immune cells. Loss of TNF signaling causes progression of tuberculosis in humans, and the increased mortality of Mycobacterium tuberculosis-infected mice is associated with disorganized necrotic granulomas, although the precise roles of TNF signaling preceding this endpoint remain undefined. We monitored transparent Mycobacterium marinum-infected zebrafish live to conduct a stepwise dissection of how TNF signaling operates in mycobacterial pathogenesis. We found that loss of TNF signaling caused increased mortality even when only innate immunity was operant. In the absence of TNF, intracellular bacterial growth and granuloma formation were accelerated and was followed by necrotic death of overladen macrophages and granuloma breakdown. Thus, TNF is not required for tuberculous granuloma formation, but maintains granuloma integrity indirectly by restricting mycobacterial growth within macrophages and preventing their necrosis.

SUBMITTER: Clay H

PROVIDER: S-EPMC3136176 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death.

Clay Hilary H Volkman Hannah E HE Ramakrishnan Lalita L

Immunity 20080801 2

Tumor necrosis factor (TNF), a key effector in controlling tuberculosis, is thought to exert protection by directing formation of granulomas, organized aggregates of macrophages and other immune cells. Loss of TNF signaling causes progression of tuberculosis in humans, and the increased mortality of Mycobacterium tuberculosis-infected mice is associated with disorganized necrotic granulomas, although the precise roles of TNF signaling preceding this endpoint remain undefined. We monitored transp ...[more]

PMID: 18691913

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Project description:The sensitization of hepatocytes to cell death from tumor necrosis factor ? (TNF?) underlies many forms of hepatic injury, including that from toxins. Critical for hepatocyte resistance to TNF? toxicity is activation of nuclear factor ?B (NF-?B) signaling, which prevents TNF?-induced death by the up-regulation of protective proteins. To further define the mechanisms of hepatocyte sensitization to TNF? killing, immunoblot analysis comparing livers from mice treated with lipopolysaccharide (LPS) alone or LPS together with the hepatotoxin galactosamine (GalN) was performed to identify TNF?-induced protective proteins blocked by GalN. Levels of CCAAT/enhancer-binding protein ? (C/EBP?) were increased after LPS treatment but not GalN/LPS treatment. In a nontransformed rat hepatocyte cell line, TNF?-induced increases in C/EBP? protein levels were dependent on NF-?B-mediated inhibition of proteasomal degradation. Pharmacological inhibition of c-Jun N-terminal kinase (JNK) did not affect C/EBP? degradation, indicating that the process was JNK-independent. C/EBP? functioned to prevent cell death as adenoviral C/EBP? overexpression blocked TNF?-induced apoptosis in cells sensitized to TNF? toxicity by NF-?B inhibition. C/EBP? inhibited TNF?-induced caspase 8 activation and downstream mitochondrial cytochrome c release and caspase 3 and caspase 7 activation. Studies in primary hepatocytes from c/ebp?(-/-) mice confirmed that loss of C/EBP? increased death from TNF?. c/ebp?(-/-) mice were also sensitized to liver injury from a nontoxic dose of LPS or TNF?. The absence of jnk2 failed to reverse the GalN-induced block in C/EBP? induction by LPS, again demonstrating that C/EBP? degradation was JNK-independent.C/EBP? is up-regulated by TNF? and mediates hepatocyte resistance to TNF? toxicity by inhibiting caspase-dependent apoptosis. In the absence of NF-?B signaling, proteasomal degradation of C/EBP? is increased by a JNK-independent mechanism and promotes death from TNF?.

Dataset Information

Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death.

Publications

Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death.

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