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
Rudolf LucasPatrick De Baetselier

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 vivo. 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 ...Continue Reading

References

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Citations

Jul 26, 2005·Infection and Immunity·Theo SternsDaniela N Männel
Feb 24, 2015·Journal of Molecular Recognition : JMR·Deysen Kerlla Fernandes Bezerra GirãoPedro Marcos Gomes Soares
Apr 9, 2010·The European Journal of Neuroscience·Antje DiestelKatharina R L Schmitt
Oct 29, 2003·American Journal of Respiratory and Critical Care Medicine·Yves Berthiaume
Nov 14, 2001·Infection and Immunity·B EchtenacherD N Männel
Mar 28, 2008·Immunological Reviews·Timo L M ten HagenAlexander M M Eggermont
Apr 15, 2020·Antioxidants & Redox Signaling·Mobarak Abu MraheilRudolf Lucas
Dec 29, 2010·Journal of Cardiovascular Disease Research·Guang YangRudolf Lucas
Jul 5, 2003·American Journal of Respiratory and Critical Care Medicine·Nadia EliaRudolf Lucas
May 15, 2001·American Journal of Physiology. Lung Cellular and Molecular Physiology·N FukudaM A Matthay
Mar 17, 2001·International Journal of Cancer. Journal International Du Cancer·R LucasL Fransen

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