Homeostatic action of interleukin-4 on endogenous and recombinant
interleukin-2-induced activated killer cell function
C Bello-Fernandez, C Bird, HE Heslop, DJ Gottlieb, JE Reittie, DM Rill, M Holland, HG Prentice and MK Brenner
Department of Haematology, Royal Free Hospital, London, England.
Cytokine-secreting, major histocompatibility complex-unrestricted activated
killer (AK) cells are toxic to a wide range of virus-infected or malignant
target cells and may be generated endogenously, eg, after bone marrow
transplantation, or by infusion of cytokines such as recombinant
interleukin-2 (rIL-2). Although AK cells secrete cytokines such as
gamma-interferon and tumor necrosis factor, which are themselves able to
recruit fresh cytokine-secreting AK cells, activation in both settings is
short-lived, implying the existence of homeostatic regulatory mechanisms.
We now demonstrate one mechanism by which rapid homeostasis is achieved. We
show that IL-4 is produced in patients with both endogenously and
exogenously generated AK cells. The cytokine was detected in serum after
marrow transplantation, and IL-4 transcripts appeared in circulating
lymphocytes during rIL-2 infusion. Although IL-4 inhibited the induction
phase of AK cell function, it had no significant inhibitory effect on the
ability of AK cells from these individuals to respond to restimulation.
Nonetheless, neutralization of the IL-4 induced during cell activation
doubled the half-life of AK function, once activating stimuli were removed,
from 18 to 44 hours and produced a 2-log increase in AK cell secretion of
tumor necrosis factor and gamma-interferon. These data suggest that IL-4
induced in vivo during lymphocyte activation abbreviates AK cell responses
once the triggering stimuli have been removed. Neutralization of endogenous
IL-4 in vivo by appropriate monoclonal antibodies might prolong the
duration of AK function.
Volume 77,
Issue 6,
pp. 1283-1289,
03/15/1991
Copyright © 1991 by The American Society of Hematology
