Multifunctional Regulation of the Biological Effects of TNF-α by the Soluble Type I and Type II TNF Receptors

doi:10.1006/cyto.1995.1004

Cytokine

Volume 7, Issue 1, January 1995, Pages 26-38

https://doi.org/10.1006/cyto.1995.1004 Get rights and content

Abstract

Two soluble receptors of tumour necrosis factor were evaluated for development as potential therapeutic agents for inflammatory disease. The recombinant human soluble Type I and Type II TNF receptors, rsTNF-RI and rsTNF-RII, were expressed at high levels in E. coli, refolded, and chromatographically purified to homogeneity. The potencies of both recombinant soluble receptors were similar to their naturally occurring soluble receptors. In in vitro cytotoxicity and competitive binding assays, both recombinant soluble receptors functioned to inhibit the biological effects of rhTNF-α although rsTNF-RI was a 5 to 30 fold more potent inhibitor of rhTNF-α than was rsTNF-RII or a truncated form of the soluble receptor, TNF-RIIΔ. In in vivo experiments in mice, rsTNF-RI was a better inhibitor than rsTNF-RIIΔ of rhTNF-α-stimulated changes in the percentages of circulating lymphocytes and neutrophils, influx of neutrophils into the peritonea) cavity, and serum IL-6 induction. At molar ratios of 0.1:1 and 0.01:1 (rsTNF-R:rhTNF-α), using the rsTNF-I or rsTNF-IIΔ, there was a trend towards enhancement of the induction of IL-6. However, higher ratios of either rsTNF-RI or rsTNF-RIIΔ significantly inhibited the rhTNF-α-stimulated increase in serum IL-6 levels. In a murine model of cytokine-induced shock, either rsTNF-RI or rsTNF-RIIΔ provided protection against the lethality of shock induced by a synergistic combination of rhTNF-α and rhIL-1β. Based on the results of these experiments, the rsTNF-RI was chosen as the better candidate for development as an anti-inflammatory agent.

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Regular ArticleMultifunctional Regulation of the Biological Effects of TNF-α by the Soluble Type I and Type II TNF Receptors

Abstract

Regular Article
Multifunctional Regulation of the Biological Effects of TNF-α by the Soluble Type I and Type II TNF Receptors