Membrane lymphotoxin-α2β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist

AbstractIn the early 1990s, it has been described that LTα and LTβ form LTα2β and LTαβ2 heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ2–LTβR system has been intensively studied while the LTα2β–TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα2β–TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα2β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα2β (memLTα2β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα2β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.

Download Full-text

Symptoms Related to Tumor Necrosis Factor Receptor 1-associated Periodic Syndrome, Multiple Sclerosis, and Severe Rheumatoid Arthritis in Patients Carrying the TNF Receptor Superfamily 1A D12E/p.Asp41Glu Mutation

The Journal of Rheumatology ◽

10.3899/jrheum.120729 ◽

2013 ◽

Vol 40 (3) ◽

pp. 261-264 ◽

Cited By ~ 3

Author(s):

JOACHIM HAVLA ◽

PETER LOHSE ◽

LISA ANN GERDES ◽

REINHARD HOHLFELD ◽

TANIA KÜMPFEL

Keyword(s):

Rheumatoid Arthritis ◽

Multiple Sclerosis ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Periodic Syndrome ◽

Tnf Receptor ◽

Autoinflammatory Disorder ◽

Inherited Mutations ◽

Necrosis Factor

Objective.Tumor necrosis factor (TNF) receptor 1–associated periodic syndrome (TRAPS) is an autoinflammatory disorder caused by autosomal dominantly inherited mutations in the TNF receptor superfamily 1A (TNFRSF1A) gene. The D12E substitution has been described only once to date, in a 4-year-old boy with fever.Methods.For DNA sequence analysis of the TNFRSF1A gene, genomic DNA was isolated, amplified by PCR, purified, and sequenced.Results.We describe 3 families (8 subjects) with the TNFRSF1A D12E substitution and TRAPS-related symptoms, in 4 cases associated with the autoimmune diseases multiple sclerosis and rheumatoid arthritis.Conclusion.The clinical phenotype might be associated with the TNFRSF1A D12E mutation. There is a close pathophysiological relationship between TNF signaling and autoimmune disorders.

Download Full-text

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

European Journal of Immunology ◽

10.1002/eji.1830270719 ◽

1997 ◽

Vol 27 (7) ◽

pp. 1719-1725 ◽

Cited By ~ 123

Author(s):

Rudolf Lucas ◽

Pierre Juillard ◽

Els Decoster ◽

Mireille Redard ◽

Danielle Burger ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Cerebral Malaria ◽

Crucial Role ◽

Tumor Necrosis ◽

Tnf Receptor ◽

Experimental Cerebral Malaria ◽

Membrane Bound ◽

Necrosis Factor

Download Full-text

Autocrine Tumor Necrosis Factor (TNF) and Lymphotoxin (LT) α Differentially Modulate Cellular Sensitivity to TNF/LT-α Cytotoxicity in L929 Cells

The Journal of Cell Biology ◽

10.1083/jcb.143.7.2057 ◽

1998 ◽

Vol 143 (7) ◽

pp. 2057-2065 ◽

Cited By ~ 10

Author(s):

Els Decoster ◽

Sigrid Cornelis ◽

Bart Vanhaesebroeck ◽

Walter Fiers

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Signal Sequence ◽

Receptor Expression ◽

Classical Pathway ◽

Tnf Receptor ◽

Endogenous Expression ◽

Membrane Bound ◽

Murine Fibrosarcoma ◽

Necrosis Factor

Tumor necrosis factor (TNF) and lymphotoxin (LT) α are structurally and functionally related cytokines. We expressed the TNF and LT-α genes in murine fibrosarcoma L929r2 cells, which can be sensitized to TNF/LT-α–dependent necrosis by inhibitors of transcription or translation. Autocrine production of murine TNF in L929r2 cells completely downmodulated the expression of the 55- and 75-kD TNF receptors, resulting in resistance to TNF/LT-α cytotoxicity. Partial downmodulation of the 55-kD receptor was observed in human TNF-producing L929r2 cells. In contrast, an unaltered TNF receptor expression was found on LT-α L929r2 transfectants. Hence, although similar cytotoxic effects are induced by extracellularly administered TNF and LT-α, endogenous expression of these cytokines fundamentally differs in the way they modulate TNF receptor expression. Unlike LT-α, secreted by the classical pathway, TNF is first formed as a membrane-bound protein, which is responsible for receptor downmodulation. To explore whether the different pathways for secretion of TNF and LT-α explain this difference, we examined the effect of membrane-bound LT-α expression. This was obtained by exchange of the classical signal sequence of LT-α for the membrane anchor of chicken hepatic lectin. Membrane retention of LT-α resulted indeed in receptor downmodulation and TNF/LT-α resistance. We conclude that membrane retention of newly synthesized TNF or LT-α is absolutely required for receptor downmodulation and TNF/LT-α resistance.

Download Full-text