Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane‐bound TNF in experimental cerebral malaria

Lucas, Rudolf; Juillard, Pierre; Decoster, Els; Redard, Mireille; Burger, Danielle; Donati, Yves; Giroud, Christian; Monso-Hinard, Christine; Kesel, Toon De; Buurman, Wim A.; Moore, Mark; Dayer, Jean‐Michel; Fiers, Walter; Bluethmann, Horst; Grau, Georges E.

doi:10.1002/eji.1830270719

Cited by 164 publications

(138 citation statements)

References 25 publications

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“…These findings implicate that the resistance of TNFR Ϫ/Ϫ mice toward Con A was not due to an impaired induction of adhesion molecules by TNF. In contrast, a resistance of TNFR2 Ϫ/Ϫ mice against experimentally induced acute cerebral malaria, which resulted from a lack of mTNF-inducible ICAM-1 expression, was recently described by Lucas et al (7). However, treatment with rmuTNF instead of Con A induced ICAM-1 and VCAM-1 only in TNFR2 Ϫ/Ϫ and wt mice, but not in TNFR1 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 86%

“…The biological actions of TNFR1 have been extensively studied (4,5), whereas the role for TNFR2, which preferentially binds the 26-kDa membrane-bound (m) 3 precursor form of soluble (s) TNF (6), is not completely understood. A previous report emphasized the in vivo relevance of TNFR2 by showing that mTNF-induced adhesion molecule expression via TNFR2 was inhibited in mice lacking this receptor (TNFR2 Ϫ/Ϫ ), but not in mice lacking TNFR1 (TNFR1 Ϫ/Ϫ ), thereby inducing resistance against experimental induced cerebral malaria (7).…”

Section: Tnf-␣-induced Expression Of Adhesion Molecules In the Liver mentioning

confidence: 99%

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TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

Wolf

Hallmann

Sass

et al. 2001

The Journal of Immunology

108

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TNF-α has been clearly identified as central mediator of T cell activation-induced acute hepatic injury in mice, e.g., Con A hepatitis. In this model, liver injury depends on both TNFRs, i.e., the 55-kDa TNFR1 as well as the 75-kDa TNFR2. We show in this report that the hepatic TNFRs are not transcriptionally regulated, but are regulated by receptor shedding. TNF directly mediates hepatocellular death by activation of TNFR1 but also induces the expression of inflammatory proteins, such as cytokines and adhesion molecules. Here we provide evidence that resistance of TNFR1−/− and TNFR2−/− mice against Con A hepatitis is not due to an impaired production of the central mediators TNF and IFN-γ. Con A injection results in a massive induction of ICAM-1, VCAM-1, and E-selectin in the liver. Lack of either one of both TNFRs did not change adhesion molecule expression in the livers of Con A-treated mice, presumably reflecting the fact that other endothelial cell-activating cytokines up-regulated adhesion molecule expression. However, treatment of TNFR1−/− and TNFR2−/− mice with murine rTNF revealed a predominant role for TNFR1 for the induction of hepatic adhesion molecule expression. Pretreatment with blocking Abs against E- and P-selectin or of ICAM−/− mice with anti-VCAM-1 Abs failed to prevent Con A hepatitis, although accumulation of the critical cell population, i.e., CD4+ T cells was significantly inhibited. Hence, up-regulation of adhesion molecules during acute hepatitis unlikely contributes to organ injury but rather represents a defense mechanism.

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Section: Discussionmentioning

confidence: 86%

Section: Tnf-␣-induced Expression Of Adhesion Molecules In the Liver mentioning

confidence: 99%

TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

Wolf

Hallmann

Sass

et al. 2001

The Journal of Immunology

108

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“…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. 38,39 Because TNFR2 Ϫ/Ϫ mice are resistant (data not shown) and TNF-R1 Ϫ/Ϫ mice are highly sensitive to LM infection, 2,3 the data suggest that membrane TNF signals through TNF-R1 to confer protection to LM infection. Further, membrane TNF has been shown to be involved in reverse (outside-to-inside) signaling.…”

Section: Discussionmentioning

confidence: 97%

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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“…While precise functional discrimination of the forms has not been made, the membrane-bound form of TNF has a unique function distinct from that of the soluble TNF. 43,44 The limited expression and range of delivery of cytokine would be critical for therapeutic purposes to avoid bystander activation. For example, while the induction of systemic toxicity due to septic shock and cachexia is the major limiting factor preventing clinical use of TNF, 7 tumor cells expressing membrane-bound form of TNF induced antitumor immunity with low toxicity.…”

Section: Figure 3 Proliferation Of T Cell Clones In Response Tomentioning

confidence: 99%

Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

Kim

Sonn

et al. 2000

Gene Ther

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Local cytokine concentrations are required for inhibition of tumor growth with less toxic side-effects. However, genetically engineered tumor cells secreting cytokines still induce toxicity and activate bystander cells. To circumvent such problems, membrane-bound forms of IL-4 (IL-4m) were expressed on MethA fibrosarcoma tumor cells. Chimeric forms of IL-4 with the type I transmembrane protein CD4 or type II transmembrane protein TNF were designed to express IL-4 in opposite orientations on the tumor cell surface. The IL-4m on tumor clones was able to support cell growth of the IL-4 dependent cytotoxic cell line (CT.4S) and

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Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane‐bound TNF in experimental cerebral malaria

Cited by 164 publications

References 25 publications

TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity

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