Immunopathologic Effects of Tumor Necrosis Factor Alpha in Murine Mycobacterial Infection Are Dose Dependent

Bekker, Linda‐Gail; Moreira, André L.; Bergtold, Amy; Freeman, Sherry; Ryffel, Bernard; Kaplan, Gilla

doi:10.1128/iai.68.12.6954-6961.2000

Cited by 164 publications

(137 citation statements)

References 32 publications

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“…However, when TNF-␣ was added back by infection with BCG-TNF, the replication of the infecting organisms was reduced and the number of viable bacteria was decreased. This was also noted in vivo: when TNF-KO mice were infected with recombinant BCG-TNF, the number of infecting BCG-TNF was reduced whereas BCG-vector grew in all organs tested (24). Similarly, in human macrophages infected in vitro with M. tuberculosis, it has been shown that when TNF-␣ is added, the cells are more efficient at curbing the growth of the bacilli than when other cytokines or cytokine combinations, including IFN-␥, are added (3).…”

Section: Discussionmentioning

confidence: 80%

“…However, the enzyme appeared to be inactive, since nitrite was not detected in the culture supernatant of infected cells, and the intracellular mycobacteria were not killed. Similarly, iNOS protein has been shown to be expressed in the macrophages of mycobacteria-infected TNF-␣ receptor gene-disrupted mice (TNFR-KO) (1) and TNF-KO mice (2,24), even in the absence of TNF-␣ or TNF-␣ signaling. However, since the infection was not controlled in all of these in vivo studies, either the enzyme was not active or it was not activated efficiently enough or early enough.…”

Section: Discussionmentioning

confidence: 99%

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TNF-α Controls Intracellular Mycobacterial Growth by Both Inducible Nitric Oxide Synthase-Dependent and Inducible Nitric Oxide Synthase-Independent Pathways

Bekker

Freeman

Murray

et al. 2001

The Journal of Immunology

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140

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The role of TNF-α in the control of mycobacterial growth in murine macrophages was studied in vitro. Infection of macrophages from TNF-α gene disrupted (TNF-knockout (KO)) mice with recombinant Mycobacterium bovis bacillus Calmette Guérin (BCG) expressing the vector only (BCG-vector) resulted in logarithmic growth of the intracellular bacilli. Infection with BCG-secreting murine TNF-α (BCG-TNF) led to bacillary killing. Killing of BCG-TNF was associated with rapid accumulation of inducible NO synthase (iNOS) protein and the production of nitrite. The uncontrolled growth of BCG-vector was associated with low iNOS expression but no nitrite production. Thus, iNOS expression appears to be TNF-α independent but iNOS generation of NO requires TNF-α. In cultures of TNF-KO macrophages infected with BCG-TNF, inhibition of iNOS by aminoguanidine (AMG) abolished the killing of the bacilli. However, the growth of the organisms was still inhibited, suggesting an iNOS-independent TNF-α-mediated growth inhibition. To confirm this, macrophages from iNOS-KO mice were infected with either BCG-vector or BCG-TNF. As expected, no nitrite was detected in the culture medium. TNF-α was detected only when the cells were infected with BCG-TNF. In the iNOS-KO macrophages, the growth of BCG was inhibited only in the BCG-TNF infection. These results suggest that in the absence of iNOS activity, TNF-α stimulates macrophages to control the growth of intracellular BCG. Thus, there appears to be both a TNF-α-dependent-iNOS-dependent killing pathway as well as a TNF-α-dependent-iNOS-independent growth inhibitory pathway for the control of intracellular mycobacteria in murine macrophages.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

TNF-α Controls Intracellular Mycobacterial Growth by Both Inducible Nitric Oxide Synthase-Dependent and Inducible Nitric Oxide Synthase-Independent Pathways

Bekker

Freeman

Murray

et al. 2001

The Journal of Immunology

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140

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“…TNF-α controls MTBC infection progression to disease as evidenced by the increase incidence of active TB in patients treated with anti-TNF-α [26,27]. However, its protective role appears to be dose dependent with increased levels promoting immunopathology [28,29]. IL-2 also is important in the host by stimulating the proliferation and differentiation of T cells and NK cells for increased effectiveness in MTBC elimination.…”

Section: Discussionmentioning

confidence: 99%

Differences in T‐cell responses between Mycobacterium tuberculosis and Mycobacterium africanum‐infected patients

et al. 2014

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In The Gambia, Mycobacterium tuberculosis (Mtb) and Mycobacterium africanum (Maf) are major causes of tuberculosis (TB). Maf is more likely to cause TB in immune suppressed individuals, implying differences in virulence. Despite this, few studies have assessed the underlying immunity to the two pathogens in human. In this study, we analyzed T-cell responses from 19 Maf-and 29 Mtb-infected HIV-negative patients before and after TB chemotherapy following overnight stimulation of whole blood with TB-specific antigens. Before treatment, percentages of early secreted antigenic target-6(ESAT-6)/culture filtrate protein-10(CFP-10) and purified protein derivative-specific single-TNF-α-producing CD4 + and CD8 + T cells were significantly higher while single-IL-2-producing T cells were significantly lower in Maf-compared with Mtb-infected patients. Purified protein derivativespecific polyfunctional CD4 + T cells frequencies were significantly higher before than after treatment, but there was no difference between the groups at both time points. Furthermore, the proportion of CD3 + CD11b + T cells was similar in both groups pretreatment, but was significantly lower with higher TNF-α, IL-2, and IFN-γ production in Mtbcompared with that of Maf-infected patients posttreatment. Our data provide evidence of differences in T-cell responses to two mycobacterial strains with differing virulence, providing some insight into TB pathogenesis with different Mtb strains that could be prospectively explored as biomarkers for TB protection or susceptibility. Keywords: Cytokines r Mycobacterium africanum r Mycobacterium tuberculosis r T cells r TuberculosisAdditional supporting information may be found in the online version of this article at the publisher's web-site 1388 Leopold D. Tientcheu et al. Eur. J. Immunol. 2014. 44: 1387-1398 TB is caused by two distinct strains Mycobacterium africanum (Maf) and Mycobacterium tuberculosis (Mtb), with Maf causing up to half of all TB [2]. In The Gambia, TB patients infected with Maf West African type 2 are more likely to be older, HIV coinfected, and/or severely malnourished [3]. In addition, their exposed household contacts have a slower rate of progression to active disease compared with their Mtb-exposed counterparts [4], suggesting that Maf might be the less virulent of the two prevalent strains [5,6]. The heterogeneity in chest x-rays, bacillary load in sputum and clinical symptoms, likely reflects the variation in host immune response to the invading pathogen, and/or the differences between the lineages within the MTBC. For instance, Maf has slower growth in culture medium compared with Mtb [6,7], which may influence progression to active disease [4].The recently published genome of Maf reveals a high content of pseudogenes and the presence of a unique sequence -the region of difference 900 "RD900" that has been deleted evolutionarily from Mtb and M. bovis strains [8]. Many studies have concentrated on the pathogen strain differences in various geographical locations, with only a few anal...

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“…13 The partial protection generated in mem-TNF mice could indicate local cell-to-cell TNF signaling by membrane-expressed TNF on T cells or macrophages at the site of infection, leading to a partial activation of the immune cells. Indeed, for the resistance to intracellular pathogens TNF must be produced locally, 36 whereas exogenous systemically administered TNF is ineffective. 37 Several biological functions of membrane TNF signaling through both TNFR1 and TNFR2 have been reported previously in vitro 9 and in vivo using transgenic mice expressing membrane TNF.…”

Section: Discussionmentioning

confidence: 99%

Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

Torres

Janot

Quesniaux

et al. 2005

The American Journal of Pathology

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Tumor necrosis factor (TNF) plays a critical role in the host response to the intracellular pathogen Listeria monocytogenes (LM). TNF exists in soluble and membrane-bound forms and exhibits both unique and overlapping activities. We examined the role of membrane TNF in the absence of secreted TNF for host resistance in knockin mice in which the endogenous TNF was replaced by a regulated, noncleavable allele (mem-TNF). Macrophages expressing mem-TNF produced nitric oxide and displayed normal bactericidal activity. Although mice completely deficient in TNF (TNF ؊/؊ ) succumbed to LM infection within 4 days, mem-TNF mice controlled LM infection at a low dose (10 4 CFU) but succumbed at a higher dose of infection (10 5 CFU). In contrast to complete TNF deficiency, mem-TNF mice developed confined microabscesses that expressed inducible nitric oxide synthase. The transfer of lymphocytes from immunized mem-TNF, but not TNF ؊/؊ , mice protected TNF ؊/؊ mice from fatal infection. Taken Protective immunity to Listeria monocytogenes (LM) infection, both in humans and experimental animals, is based on orchestrated action of T cells, macrophages, and cytokines, including interferon (IFN)-␥, interleukin (IL)-12, and tumor necrosis factor (TNF). 1 A critical role for TNF in anti-LM defense is inferred from neutralization and gene deletion experiments in mice. 2,3 In addition, the TNFrelated cytokines lymphotoxin (LT)-␣ and LT-␤ are also required to control LM infection. 4 Both secreted TNF and LT-␣ signal through p55 and p75 TNF receptors (TNFR1 and TNFR2, respectively). The cell-bound LT-␣␤ heterotrimers recognize the LT-␤R. TNF-R1 signaling appears to be critical for the control of LM infection 2,3 and LT-␤R also plays a distinct role, while the contribution of TNFR2 is less well defined.TNF is expressed by a variety of cells, including macrophages and T cells, and is a major regulator of inflammation and leukocyte trafficking. 5 TNF is first produced as an integral membrane protein and is subsequently cleaved by the metalloproteinase-disintegrin TACE (TNF-␣ converting enzyme) 6,7 into the secreted trimeric TNF. Although the role of TNF in controlling intracellular bacterial infections is uncontested, the function of membrane TNF in host resistance is less understood.Several biological functions of membrane TNF have been described, such as cytotoxicity, polyclonal activation of B cells, induction of IL-10 by monocytes, induction of chemokines, and ICAM-1 expression on endothelial cells. 8 -10 The transgenic overexpression of membrane TNF has demonstrated an in vivo role in the control of LM and mycobacterial infection. [11][12][13] However, these models were potentially nonphysiological as transgenic expression of a membrane-only form of TNF results in artificially high and nonselective expression of membrane TNF. The recent generation of mice with functional, normally regulated and expressed membrane-bound TNF, obtained by knocking-in an uncleavable ⌬1-9, K11E TNF allele (mem-TNF mice), represents a major advance and allo...

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Immunopathologic Effects of Tumor Necrosis Factor Alpha in Murine Mycobacterial Infection Are Dose Dependent

Cited by 164 publications

References 32 publications

TNF-α Controls Intracellular Mycobacterial Growth by Both Inducible Nitric Oxide Synthase-Dependent and Inducible Nitric Oxide Synthase-Independent Pathways

TNF-α Controls Intracellular Mycobacterial Growth by Both Inducible Nitric Oxide Synthase-Dependent and Inducible Nitric Oxide Synthase-Independent Pathways

Differences in T‐cell responses between Mycobacterium tuberculosis and Mycobacterium africanum‐infected patients

Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

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