Disruption by Interferon-alpha of an Autocrine Interleukin-6 Growth Loop in IL-6-dependent U266 Myeloma Cells by Homologous and Heterologous Down-regulation of the IL-6 Receptor Alpha- and Beta-chains

Overview

Journal J Clin Invest

Specialty General Medicine

Date 1994 Dec 1

PMID 7989587

Citations 11

Authors

M Schwabe

A T Brini

M C Bosco

F Rubboli

M Egawa

J Zhao

G L Princler

H F Kung

Affiliations

Soon will be listed here.

Abstract

IL-6 is an autocrine growth factor for U266 myeloma cells and their growth is inhibited by IFN-alpha or IL-6 mAb. We asked, therefore, whether IFN-alpha-induced growth inhibition involved IL-6. IFN-alpha and mAb against IL-6, the IL-6R alpha-(gp80) or beta-chain (gp130) potently inhibited U266 cells. Remarkably, this effect occurred despite IFN-alpha-augmented secretion of endogenous IL-6. However, examining the IL-6R revealed that IFN-alpha drastically curtailed expression of the IL-6R alpha- and beta-chain. This effect occurred on two different levels (protein and mRNA) and by two different mechanisms (directly and indirectly through IL-6). First, IFN-alpha, but not IL-6, greatly decreased gp80 and, to a lesser extent, gp130 mRNA levels which resulted in a loss of IL-6 binding sites. Second, IFN-alpha-induced IL-6 predominantly down-regulated membrane-bound gp130. IFN-alpha-mediated decrease of gp80 levels was not detected on IL-6-independent myeloma (RPMI 8226) or myeloid cells (U937). We conclude that IFN-alpha inhibited IL-6-dependent myeloma cell growth by depriving U266 cells of an essential component of their autocrine growth loop, a functional IL-6R.

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