The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor

Grell, Matthias; Douni, Eleni; Wajant, Harald; Löhden, Matthias; Clauss, Matthias; Maxeiner, Beate; Georgopoulos, Spiros; Lesslauer, Werner; Kollias, George; Pfizenmaier, Klaus; Scheurich, Peter

doi:10.1016/0092-8674(95)90192-2

Cited by 1,241 publications

(940 citation statements)

References 37 publications

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“…The membrane bound form could be associated to a more complex co-signaling yielded by the association with other surface molecules. This would suggest that both forms display di erential biological activities, as described for other cytokines (Grell et al, 1995). The present studies demonstrate that IL-15 secreted by normal CD34 + cells is not e cient to trigger NK di erentiation.…”

Section: Discussionsupporting

confidence: 58%

Altered natural killer cell differentiation in CD34+ progenitors from Chronic Myeloid Leukemia patients

et al. 2000

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IL-15 and SCF fail to induce NK di erentiation and proliferation of CD34 + hematopoietic progenitors from chronic myeloid leukemia patients in contrast to normal stem cells although, both normal and leukemic CD34 + cells display comparable expression of c-kit or IL-15 receptor subunits. Interestingly, confocal microscopy analysis revealed that leukemic and most normal CD34 + cells produce and secrete IL-15, as shown by its tra cking through the Golgi apparatus and early endosomes. However, only leukemic progenitors express the membrane bound IL-15. Colocalization and internalization of IL-15Rb/gc and IL-15Ra/gc complexes indicated that IL-15 was speci®cally uptaken by leukemic progenitors. We also demonstrated that in both normal and leukemic progenitors, the signaling kinase Jak3 is constitutively pre-associated with the gc chain. Anti-IL-15 neutralizing mAb treatment resulted in downregulation of gc chain and disruption of gc/Jak3 interaction in normal but had no e ect in leukemic progenitors. Our results suggest the existence in both normal and leukemic CD34 + cells of a constitutive production of a bioactive IL-15 that does not lead to NK di erentiation and further indicate that membrane bound IL-15 and constitutive activation of gc are hallmarks of leukemic progenitors.

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Section: Discussionsupporting

confidence: 58%

Altered natural killer cell differentiation in CD34+ progenitors from Chronic Myeloid Leukemia patients

et al. 2000

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“…Soluble TNF binds with higher affinity to TNFR1 7 while transmembrane TNF primarily signals through TNFR2. 8 Although TNFR1-mediated signaling is well known for its pro-inflammatory and apoptosis-inducing capacities, the signaling through TNFR2 is less well understood. Moreover, transmembrane TNF by itself may lead to intracellular signaling, 9 making the TNF-induced signaling program even more complex.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomics of infliximab treatment using peripheral blood cells of patients with rheumatoid arthritis

et al. 2010

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“…TNF is bioactive both as a transmembrane protein and as a homotrimeric secreted molecule [5] and mediates its effects through two distinct TNF receptors, p55TNFR (TNFRI) and p75TNFR (TNFRII) [6]. Transmembrane TNF (tmTNF) appears superior to soluble TNF in activating the p75TNFR, while at physiological concentrations soluble TNF primarily activates the p55TNFR [7]. The two types of TNF receptors share structural homology in the extracellular TNF-binding domains, but they induce separate cytoplasmic signaling pathways following receptor-ligand interaction [8].…”

Section: Introductionmentioning

confidence: 99%

Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity

et al. 2006

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Using targeted mutagenesis in mice, we have blocked shedding of endogenous murine TNF by deleting its cleavage site. Mutant mice produce physiologically regulated levels of transmembrane TNF (tmTNF), which suffice to support thymocyte proliferation but cannot substitute for the hepatotoxic activities of wild-type TNF following LPS/Dgalactosamine challenge in vivo and are not sufficient to support secondary lymphoid organ structure and function. Notably, however, tmTNF is capable of exerting antiListerial host defenses while remaining inadequate to mediate arthritogenic functions, as tested in the tristetraprolin-deficient model of TNF-dependent arthritis. Most interestingly, in the EAE model of autoimmune demyelination, tmTNF suppresses disease onset and progression and retains the autoimmune suppressive properties of wild-type TNF. Together, these results indicate that tmTNF preserves a subset of the beneficial activities of TNF while lacking detrimental effects. These data support the hypothesis that selective targeting of soluble TNF may offer several advantages over complete blockade of TNF in the treatment of chronic inflammation and autoimmunity.Supporting information for this article is available at: http://www.wiley-vch.de/contents/jc_2040/2006/35921_s.pdf IntroductionOriginally identified as an endotoxin-induced serum factor that causes necrosis of tumors [1] and/or cachexia [2], TNF is currently known to mediate a wide array of biological activities [3, 4]. TNF is produced in response to bacterial toxins, inflammatory products and other stimuli mainly by cells of the myeloid lineage, with additional producers including B and T lymphocytes, NK cells, microglia, astrocytes and adipocytes [3]. TNF is bioactive both as a transmembrane protein and as a homotrimeric secreted molecule [5] and mediates its effects through two distinct TNF receptors, p55TNFR (TNFRI) and p75TNFR (TNFRII) [6]. Transmembrane TNF (tmTNF) appears superior to soluble TNF in activating the p75TNFR, while at physiological concentrations soluble TNF primarily activates the p55TNFR [7]. The two types of TNF receptors share structural homology in the extracellular TNF-binding domains, but they induce separate cytoplasmic signaling pathways following receptor-ligand interaction [8]. Apoptosis and activation of NF-jB are initiated by p55TNFR, whereas p75TNFR appears to play a direct role in only a limited number of TNF responses [6,9]. Several functionally diverse proteins, such as growth factors and cytokines and including TNF, are initially synthesized as biologically active membrane-anchored molecules that are subsequently released from the cell by proteolysis [10]. Thus, surface localization may serve to restrict activity to specific microenvironments, whereas release may lead to distal effects. TNF is synthesized as a 26 kDa type II transmembrane molecule, which can be processed by a TNF-alpha converting enzyme (TACE or ADAM17), to generate secreted 17 kDa monomers that form biologically active homotrimers [11,12]. Indications for a r...

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The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor

Cited by 1,241 publications

References 37 publications

Altered natural killer cell differentiation in CD34+ progenitors from Chronic Myeloid Leukemia patients

Altered natural killer cell differentiation in CD34+ progenitors from Chronic Myeloid Leukemia patients

Pharmacogenomics of infliximab treatment using peripheral blood cells of patients with rheumatoid arthritis

Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity

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