Journal of Experimental Medicine, Vol 171, 681-693, Copyright © 1990 by Rockefeller University Press
A serum factor that suppresses the cytotoxic function of cytokine- stimulated human eosinophils
DS Silberstein, MS Minkoff, AA Creasey and JR David
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
A human subject (NR) was identified whose eosinophils and neutrophils
failed to respond to TNF in vitro in 29 of 33 experiments, using several
biological assays. There was a response rate to TNF of 100% among 37
control subjects whose leukocytes were tested in parallel. NR serum
contained an activity that inhibited the cytotoxic function of TNF- and
GM-CSF-stimulated normal human eosinophils. A similar activity was detected
in 4 of 122 control sera and in sera of two subjects with
hypereosinophilia. This activity (ECI) had an apparent molecular weight of
80,000-100,000 and was sensitive to heating at 80 degrees C or to trypsin
treatment. HPLC sizing chromatography increased the titer of ECI by a
factor of 50 to 2,000 in experiments using NR serum or other sera with
detectable inhibitory activity. In seven experiments using sera with no
inhibitory activity, HPLC generated ECI of the same apparent molecular
weight. The effect of HPLC on ECI activity required the separation of serum
components and did not result from exposure to HPLC system components or
other sample processing methods. This suggests that ECI in serum can be
stabilized in an inactive or partially active form and that HPLC removes
the stabilizing component. ECI suppressed TNF-stimulated eosinophil
cytotoxic function when added to cultures up to 4 h after exposure of
eosinophils to cytokine. However, ECI did not protect L929 cells from the
toxic effects of TNF. Thus, ECI did not act by preventing the initial
interaction of TNF with eosinophils or by interfering with the binding of
TNF to its receptor on L929 cells. The results suggest that ECI is a
component of a feedback mechanism that suppresses functions of
cytokine-activated eosinophils in inflammation.
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