Generation of a mouse tumor necrosis factor mutant with antiperitonitis and desensitization activities comparable to those of the wild type but with reduced systemic toxicity

Rudolf Lucas, B. Echtenacher, E. Sablon, P. Juillard, S. Magez, J. Lou, Y. Donati, F. Bosman, A. Van de Voorde, L. Fransen, D. N. Männel, G. E. Grau, P. De Baetselier

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

In this study, we investigated whether the recently identified lectin- like domain of tumor necrosis factor (TNF) is implicated in its biological activities on mammalian cells. To this end, a mouse TNF (mTNF) triple mutant, T104A-E106A-E109A mTNF (referred to hereafter as triple mTNF), lacking the lectin-like affinity of mTNF for specific oligosaccharides, was compared with the wild-type molecule for various TNF effects in vitro and in viva. The triple mTNF displayed a 50-fold-reduced TNF receptor 2 (TNFR2)-mediated bioactivity but only a 5-fold-reduced TNFR1-mediated bioactivity in vitro. The specific activity of the triple mutant on L929 fibrosarcoma cells was slightly reduced compared with that of the wild type. We subsequently assessed the systemic toxicity of triple versus wild-type mTNF, since TNFR2 is partially implicated in this activity. The triple mTNF had a significantly reduced toxicity compared with that of wild-type mTNF in vivo. Moreover, we compared the effects of the triple and the wild-type mTNFs in TNFR1-mediated phenomena, such as (i) induction of tolerance towards a lethal mTNF dose and (ii) protective activity in cecal ligation and puncture-induced septic peritonitis. No significant differences between the mutant and wild-type forms were observed. In conclusion, these results indicate that triple mTNF, lacking TNF's lectin-like binding capacity, has reduced systemic toxicity but retains the tolerance-inducing and peritonitis-protective activities of wild- type mTNF.

Original languageEnglish (US)
Pages (from-to)2006-2010
Number of pages5
JournalInfection and Immunity
Volume65
Issue number6
StatePublished - Jun 18 1997
Externally publishedYes

Fingerprint

Tumor Necrosis Factor-alpha
Lectins
Receptors, Tumor Necrosis Factor, Type I
Peritonitis
Receptors, Tumor Necrosis Factor, Type II
Fibrosarcoma
Tumor Necrosis Factor Receptors
Oligosaccharides
Punctures
Ligation

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

Generation of a mouse tumor necrosis factor mutant with antiperitonitis and desensitization activities comparable to those of the wild type but with reduced systemic toxicity. / Lucas, Rudolf; Echtenacher, B.; Sablon, E.; Juillard, P.; Magez, S.; Lou, J.; Donati, Y.; Bosman, F.; Van de Voorde, A.; Fransen, L.; Männel, D. N.; Grau, G. E.; De Baetselier, P.

In: Infection and Immunity, Vol. 65, No. 6, 18.06.1997, p. 2006-2010.

Research output: Contribution to journalArticle

Lucas, R, Echtenacher, B, Sablon, E, Juillard, P, Magez, S, Lou, J, Donati, Y, Bosman, F, Van de Voorde, A, Fransen, L, Männel, DN, Grau, GE & De Baetselier, P 1997, 'Generation of a mouse tumor necrosis factor mutant with antiperitonitis and desensitization activities comparable to those of the wild type but with reduced systemic toxicity', Infection and Immunity, vol. 65, no. 6, pp. 2006-2010.
Lucas, Rudolf ; Echtenacher, B. ; Sablon, E. ; Juillard, P. ; Magez, S. ; Lou, J. ; Donati, Y. ; Bosman, F. ; Van de Voorde, A. ; Fransen, L. ; Männel, D. N. ; Grau, G. E. ; De Baetselier, P. / Generation of a mouse tumor necrosis factor mutant with antiperitonitis and desensitization activities comparable to those of the wild type but with reduced systemic toxicity. In: Infection and Immunity. 1997 ; Vol. 65, No. 6. pp. 2006-2010.
@article{617a911e869d4f1fbfc26abf1aa00732,
title = "Generation of a mouse tumor necrosis factor mutant with antiperitonitis and desensitization activities comparable to those of the wild type but with reduced systemic toxicity",
abstract = "In this study, we investigated whether the recently identified lectin- like domain of tumor necrosis factor (TNF) is implicated in its biological activities on mammalian cells. To this end, a mouse TNF (mTNF) triple mutant, T104A-E106A-E109A mTNF (referred to hereafter as triple mTNF), lacking the lectin-like affinity of mTNF for specific oligosaccharides, was compared with the wild-type molecule for various TNF effects in vitro and in viva. The triple mTNF displayed a 50-fold-reduced TNF receptor 2 (TNFR2)-mediated bioactivity but only a 5-fold-reduced TNFR1-mediated bioactivity in vitro. The specific activity of the triple mutant on L929 fibrosarcoma cells was slightly reduced compared with that of the wild type. We subsequently assessed the systemic toxicity of triple versus wild-type mTNF, since TNFR2 is partially implicated in this activity. The triple mTNF had a significantly reduced toxicity compared with that of wild-type mTNF in vivo. Moreover, we compared the effects of the triple and the wild-type mTNFs in TNFR1-mediated phenomena, such as (i) induction of tolerance towards a lethal mTNF dose and (ii) protective activity in cecal ligation and puncture-induced septic peritonitis. No significant differences between the mutant and wild-type forms were observed. In conclusion, these results indicate that triple mTNF, lacking TNF's lectin-like binding capacity, has reduced systemic toxicity but retains the tolerance-inducing and peritonitis-protective activities of wild- type mTNF.",
author = "Rudolf Lucas and B. Echtenacher and E. Sablon and P. Juillard and S. Magez and J. Lou and Y. Donati and F. Bosman and {Van de Voorde}, A. and L. Fransen and M{\"a}nnel, {D. N.} and Grau, {G. E.} and {De Baetselier}, P.",
year = "1997",
month = "6",
day = "18",
language = "English (US)",
volume = "65",
pages = "2006--2010",
journal = "Infection and Immunity",
issn = "0019-9567",
publisher = "American Society for Microbiology",
number = "6",

}

TY - JOUR

T1 - Generation of a mouse tumor necrosis factor mutant with antiperitonitis and desensitization activities comparable to those of the wild type but with reduced systemic toxicity

AU - Lucas, Rudolf

AU - Echtenacher, B.

AU - Sablon, E.

AU - Juillard, P.

AU - Magez, S.

AU - Lou, J.

AU - Donati, Y.

AU - Bosman, F.

AU - Van de Voorde, A.

AU - Fransen, L.

AU - Männel, D. N.

AU - Grau, G. E.

AU - De Baetselier, P.

PY - 1997/6/18

Y1 - 1997/6/18

N2 - In this study, we investigated whether the recently identified lectin- like domain of tumor necrosis factor (TNF) is implicated in its biological activities on mammalian cells. To this end, a mouse TNF (mTNF) triple mutant, T104A-E106A-E109A mTNF (referred to hereafter as triple mTNF), lacking the lectin-like affinity of mTNF for specific oligosaccharides, was compared with the wild-type molecule for various TNF effects in vitro and in viva. The triple mTNF displayed a 50-fold-reduced TNF receptor 2 (TNFR2)-mediated bioactivity but only a 5-fold-reduced TNFR1-mediated bioactivity in vitro. The specific activity of the triple mutant on L929 fibrosarcoma cells was slightly reduced compared with that of the wild type. We subsequently assessed the systemic toxicity of triple versus wild-type mTNF, since TNFR2 is partially implicated in this activity. The triple mTNF had a significantly reduced toxicity compared with that of wild-type mTNF in vivo. Moreover, we compared the effects of the triple and the wild-type mTNFs in TNFR1-mediated phenomena, such as (i) induction of tolerance towards a lethal mTNF dose and (ii) protective activity in cecal ligation and puncture-induced septic peritonitis. No significant differences between the mutant and wild-type forms were observed. In conclusion, these results indicate that triple mTNF, lacking TNF's lectin-like binding capacity, has reduced systemic toxicity but retains the tolerance-inducing and peritonitis-protective activities of wild- type mTNF.

AB - In this study, we investigated whether the recently identified lectin- like domain of tumor necrosis factor (TNF) is implicated in its biological activities on mammalian cells. To this end, a mouse TNF (mTNF) triple mutant, T104A-E106A-E109A mTNF (referred to hereafter as triple mTNF), lacking the lectin-like affinity of mTNF for specific oligosaccharides, was compared with the wild-type molecule for various TNF effects in vitro and in viva. The triple mTNF displayed a 50-fold-reduced TNF receptor 2 (TNFR2)-mediated bioactivity but only a 5-fold-reduced TNFR1-mediated bioactivity in vitro. The specific activity of the triple mutant on L929 fibrosarcoma cells was slightly reduced compared with that of the wild type. We subsequently assessed the systemic toxicity of triple versus wild-type mTNF, since TNFR2 is partially implicated in this activity. The triple mTNF had a significantly reduced toxicity compared with that of wild-type mTNF in vivo. Moreover, we compared the effects of the triple and the wild-type mTNFs in TNFR1-mediated phenomena, such as (i) induction of tolerance towards a lethal mTNF dose and (ii) protective activity in cecal ligation and puncture-induced septic peritonitis. No significant differences between the mutant and wild-type forms were observed. In conclusion, these results indicate that triple mTNF, lacking TNF's lectin-like binding capacity, has reduced systemic toxicity but retains the tolerance-inducing and peritonitis-protective activities of wild- type mTNF.

UR - http://www.scopus.com/inward/record.url?scp=0030962992&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030962992&partnerID=8YFLogxK

M3 - Article

VL - 65

SP - 2006

EP - 2010

JO - Infection and Immunity

JF - Infection and Immunity

SN - 0019-9567

IS - 6

ER -