Effects of interferon α on autocrine growth factor loops in B lymphoproliferative disorders

Helen E. Heslop, Alessandra C.M. Bianchi, Frank T. Cordingley, Martin Turner, W. Chandima P. De Mel, A. Victor Hoflbrand, Malcolm K. Brenner

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

The B lymphoproliferative disorders B chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) produce a number of autocrine growth factors, including tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-1, all of which may induce positive feedback growth loops. If such malignancies depend on these autocrine growth loops for survival, their interruption may be therapeutically valuable. Interferon α (IFN-α) abrogates TNF- or IL-6-induced proliferation of HCL and B-CLL cells in vitro and has therapeutic activity in these diseases. We have investigated the possibility that IFN-α may act by interrupting autocrine growth factor loops. If purified B-CLL or HCL cells are cultured in the presence of TNF, there is induction of mRNA for TNF, IL-1α, IL-1β, and IL-6. However, culture in the presence of IFN-α in addition to TNF reduced the level of mRNA for all these cytokines, compared with cells cultured in TNF alone. While cytokine mRNA levels were diminished, levels of mRNA for the ribonuclease activator 2-5A synthetase were increased. Analysis of the kinetics of cytokine mRNA production showed that levels fall shortly after the rise of 2-5A synthetase mRNA. IFN-α may produce these effects by shortening the half-life of cytokine mRNA, since TNF mRNA half-life in B-CLL and HCL cells is substantially reduced when the cells are cultured with IFN-α. These data suggest that IFN-α may mediate its therapeutic effects in these malignancies by blocking autocrine growth factor loops.

Original languageEnglish (US)
Pages (from-to)1729-1734
Number of pages6
JournalJournal of Experimental Medicine
Volume172
Issue number6
DOIs
StatePublished - Dec 1 1990

ASJC Scopus subject areas

  • Medicine(all)

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