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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1717-1726
Suppression of Interleukin-12 Production by Human Monocytes After
Preincubation With Lipopolysaccharide
Miriam Wittmann,
Vivi-Ann Larsson,
Petra Schmidt,
Gabriele Begemann,
Alexander Kapp, and
Thomas Werfel
From Hannover Medical University, Department of Dermatology and
Allergology, Hannover, Germany.
Interleukin-12 (IL-12) is a potent proinflammatory and
immunoregulatory cytokine skewing T lymphocytes to express a type 1 cytokine pattern. Optimal expression of IL-12 mRNA and bioactivity in
vitro requires specific priming of monocytes by interferon- (IFN-) or granulocyte-macrophage colony-stimulating factor (GM-CSF) before lipopolysaccharide (LPS) stimulation. We show here for the first
time that the production of IL-12 by IFN-- or GM-CSF-primed human
monocytes can be completely suppressed by preincubation with LPS (from
Escherichia coli Serotype 055:B5) for 6 to 24 hours before the
priming procedure. A dose-dependent suppression of IL-12p70 was
measured on the levels of intracellular cytokine production and
cytokine secretion. mRNA studies on the expression of p40 and p35
showed an LPS-induced downregulation of both subunits. The results of
several different experimental approaches suggest that IL-12
downregulation was not due to endogenous IL-10, IL-4, prostaglandin
E2 (PGE2), tumor necrosis factor- (TNF-),
or nitric oxide (NO) production induced by LPS. Moreover,
preincubation of monocytes with LPS did not lead to a downregulation of
the CD14 antigen, which is an LPS receptor. LPS preincubation in this experimental setting did not result in a general hyporesponsiveness of
the monocytes, as IL-6 production as well as IFN--induced upregulation of CD54 did not decline. Downregulation of IL-12 was not
due to changes in mRNA stability. These findings show that the
immunoregulatory important cytokine, IL-12, underlies itself a complex regulation.
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