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The Interferon Refractory State

II. Biological Characterization of a Refractoriness-Inducing Protein^1,2,

From the Oncology Center, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Abstract

When L929 cells were treated with samples collected from cells or mice producing interferon, almost complete refractoriness to subsequent interferon induction was observed. The relationship of this refractoriness-inducing product (RIP)⁵ to the antiviral activity of the samples was determined. Using interferon in the pretreatment sample as a measure of RIP concentration, a semilog plot of the pretreatment interferon titer and interferon subsequently produced, resulted in an approximately linear relationship between 10 and 100 units of interferon in the pretreatment sample. This relationship was largely independent of the multiplicity of Newcastle disease virus (NDV) used to produce interferon in the treated monolayers.

A 2- to 6-fold temporal differentiation in the refractoriness-inducing activity and the antiviral activities was obtained both in vitro and in vivo. Supernatants collected 48 hr after NDV infection of L929 cells had 2- to 4-fold more refractoriness-inducing activity than those collected earlier. In serum of ICR mice given poly rI_n:rC_n-poly-d-lysine, a quantitatively similar temporal increase in refractoriness-inducing activity was observed. Treatment of L929 cells with cycloheximide resulted in a 4-fold increase in interferon production. At equivalent interferon concentrations, supernatants from the cycloheximide-treated monolayers inhibited interferon production 4-fold less than did comparable supernatants from non-cycloheximide-treated monolayers. Soluble cell extracts inhibited interferon production to a greater degree than did extracellular preparations. The protein nature of the refractoriness-inducing activity was suggested by its trypsin sensitivity. These findings suggest that the refractoriness-inducing and antiviral activities of interferon preparations result from different proteins.

Footnotes

¹ A portion of this work was presented at the American Society of Microbiology Annual Meeting, April 24, 1972.

² Supported in part by Jane Coffin Childs Fund Grant 286, United States Public Health Service, National Cancer Institute Regional Oncology Research Grant CA06973, and National Institute of Allergy and Infectious Diseases Grant AI-11292-01.

⁵ Abbreviations used in this paper: NDV, Newcastle disease virus; RIP, refractoriness-inducing product; MEM, Eagle's minimal essential medium; FCS, fetal calf serum; VSV, vesicular stomatitis virus; NDV-UV, ultraviolet irradiated NDV; EBSS, Earle's balanced salt solution.

³ Present address: Division of Clinical Oncology, 701C University Hospitals, 1300 University Avenue, Madison, Wisconsin 53706.

⁴ Present address: Department of Medical Oncology, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, New York 14203.