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Release of interleukin-12 in experimental Escherichia coli septic shock in
baboons: relation to plasma levels of interleukin-10 and interferon- gamma
PM Jansen, TC van der Pouw Kraan, IW de Jong, G van Mierlo, J Wijdenes, AA Chang, LA Aarden, FB Taylor and CE Hack
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service,
Amsterdam, The Netherlands.
Interleukin (IL)-12 is thought to be a key factor for the induction of
interferon gamma (IFN-gamma), a cytokine essential for the lethal effects
of endotoxin. We report here on the release of the nonfunctional subunit of
IL-12, p40, as well as biologically active heterodimeric IL-12, p70, after
administration of a lethal (n = 5) or sublethal (n = 8) dose of live
Escherichia coli to baboons. Remarkably, on lethal challenge, peak levels
of p40 were observed at 3 hours that were about twofold lower than those
elicited after sublethal challenge (2,813 +/- 515 pg/mL v 4,972 +/- 732
pg/mL, P < .05). This disparity was also observed, although to a lesser
extent, for IL-12 p70 antigen, of which maximum levels of 91 +/- 47 pg/mL
and 151 +/- 41 pg/mL were measured 6 hours after a lethal or sublethal dose
of E coli, respectively. Circulating p70 antigen correlated with IL-12
biologic activity (r = 0.869; P < .001). When comparing lethal to
sublethal conditions, lower peak levels of IL-12 on lethal E coli sharply
contrasted with higher levels of other proinflammatory cytokines, such as
tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 observed in
these animals. Lower IL-12 concentrations in the lethal group may have
resulted in part from the enhanced production of IL-10, a known inhibitor
of IL-12 synthesis in vitro, as peak levels of this cytokine 3 hours
postchallenge inversely correlated with peak levels of IL-12, in particular
p40 (r = -0.802; P < .01). Contrary to what might be expected if
IFN-gamma were solely induced by IL-12, lethally challenged baboons
generated threefold more IFN-gamma at 6 hours than those receiving a
sublethal dose (P < .05). Moreover, higher levels of IFN- gamma were
associated with lower p40/p70 ratios, suggesting that, in agreement with
observations in vitro, IFN-gamma may have preferentially upregulated the
release of p70 over p40. These data show that IL-12 is released in
experimental septic shock in nonhuman primates and suggest that IL-10 and
IFN-gamma are involved in the regulation of this release. Furthermore, this
study indicates that the systemic release of IL-12 might be essential, but
is not likely sufficient, to promote lethal production of IFN-gamma in
sepsis.
Volume 87,
Issue 12,
pp. 5144-5151,
06/15/1996
Copyright © 1996 by The American Society of Hematology
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