Outside-to-Inside Signal Through the Membrane TNF-α Induces E-Selectin (CD62E) Expression on Activated Human CD4+ T Cells

Harashima, Shin‐ichi; Horiuchi, Takahiko; Hatta, Nobuaki; Morita, Chika; Higuchi, Masanori; Sawabe, Takuya; Tsukamoto, Hiroshi; Tahira, Tomoko; Hayashi, Kenshi; Fujita, Shigeru; Niho, Yoshiyuki

doi:10.4049/jimmunol.166.1.130

Cited by 119 publications

(95 citation statements)

References 39 publications

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“…On ligation of the receptor, mem-TNF-expressing cells are activated to express Eselectin. 40 Thus, membrane TNF in T cells might function as a bipolar positive regulator of inflammation, either transmitting signals as a ligand to target cells or receiving signals through membrane TNF itself into T cells.…”

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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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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“…When tmTNF is transfected into cells, investigators take care to protect it from an enzyme that would otherwise cleave the TNF molecule, called TNFα-converting enzyme (TACE) [67]. At first the gene encoding tmTNF was transfected as a deletion mutant, but more recently, Harashima et al [68] developed a method of transfecting cells with a tmTNF rendered non-cleavable by site-directed mutagenesis. Using these methods, investigators assessed the number of anti-TNF molecules that can bind tmTNF either by flow cytometry or by radioassay [16].…”

Section: Limiting Factors Contributing To Disease Restriction In Thermentioning

confidence: 99%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

260

162

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Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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“…9a). For several membrane-anchored cytokines, such signal transduction mechanisms have been described previously (13)(14)(15)(16)(17)(18). To explore the contribution of reverse mTNF signaling in monocytes to T cell-dependent TNF-␣ production, the potential counterpart of mTNF, namely, TNFR2, on the T cell surface was blocked.…”

Section: Reverse Signaling Of Mtnf On Monocyte Surfaces Contributes Tmentioning

confidence: 99%

“…It can be hypothesized that surface TNFR molecules are able to ligate mTNF on the opposing cell and subsequently trigger signal transduction from the mTNF molecule to the nucleus. Such so-called reverse signaling, the transfer of signals following ligation of membrane-anchored cytokines, has been described for several members of the TNF superfamily including TNF-␣ (13)(14)(15)(16)(17)(18). Ligation of mTNF by soluble receptor constructs induces dephosphorylation of the small cytoplasmic part of mTNF, which is crucial for mTNF-mediated calcium signaling (18).…”

mentioning

confidence: 99%

Interaction between Transmembrane TNF and TNFR1/2 Mediates the Activation of Monocytes by Contact with T Cells

Rossol

Meusch

Pierer

et al. 2007

The Journal of Immunology

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Monocytes and monocytic cells produce proinflammatory cytokines upon direct cell contact with activated T cells. In the autoimmune disease rheumatoid arthritis, the pivotal role of TNF-α implies that the interaction between transmembrane TNF-α (mTNF) and the TNF receptors (TNFR1 and TNFR2) might participate in the T cell contact-dependent activation of monocytes. Accordingly, treatment of rheumatoid arthritis by administration of a TNF-α-blocking Ab was found to significantly decrease TNF-α production by monocytes. Several lines of evidence indicated that signaling through TNFR1/2 and through mTNF (reverse signaling) is involved in TNF-α production by monocytes after T cell contact: 1) blocking mTNF on activated T cells leads to a significant reduction in TNF-α production; 2) down-regulation of TNFR1/2 on monocytes by transfection with small interfering RNA results in diminished TNF-α production; 3) blocking or down-regulating TNFR2 on activated T cells inhibits TNF-α production, indicating that mTNF on the monocyte surface mediates signaling; 4) ligation of mTNF on monocytes by surface TNFR2 transfected into resting T cells induces TNF-α production due to reverse signaling by mTNF; and 5) ligation of mTNF on monocytes by a soluble TNFR2:Ig receptor construct induces TNF-α production due to reverse signaling. In conclusion, we identified mTNF and TNFR1/2 as interaction partners contributing to TNF-α production in monocytes. Both pathways initiated by mTNF-TNFR interaction are likely to be inhibited by treatment with anti-TNF-α Abs.

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Outside-to-Inside Signal Through the Membrane TNF-α Induces E-Selectin (CD62E) Expression on Activated Human CD4+ T Cells

Cited by 119 publications

References 39 publications

Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

TNFα blockade in human diseases: Mechanisms and future directions

Interaction between Transmembrane TNF and TNFR1/2 Mediates the Activation of Monocytes by Contact with T Cells

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