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Recombinant C5a stimulates transcription rather than translation of
interleukin-1 (IL-1) and tumor necrosis factor: translational signal
provided by lipopolysaccharide or IL-1 itself
R Schindler, JA Gelfand and CA Dinarello
Department of Medicine, Tufts University School of Medicine, Boston, MA.
We investigated the effects of recombinant C5a (rC5a) on gene expression
and synthesis of interleukin-1 beta (IL-1 beta) and tumor necrosis factor
(TNF) in fresh human peripheral blood mononuclear cells (PBMC). Total
(cell-associated and secreted) cytokine synthesis was measured. In the
strict absence of endotoxin (lipopolysaccharide [LPS]), rC5a resulted in a
small but statistically insignificant increase in immunoreactive IL-1 beta
and TNF, as well as in IL-1 and IL- 6 bioactivity. On the other hand, rC5a
induced marked transcriptional activation of IL-1 beta and TNF in a
dose-dependent fashion with an optimal concentration of 50 ng/mL. The
rC5a-induced cytokine messenger RNA (mRNA) was not spontaneously translated
into protein. At 50 ng/mL, rC5a induced the same levels of mRNA for IL-1
beta and TNF as 1 ng/mL of LPS, whereas LPS induced 12 times more IL-1 beta
protein and 70 times more TNF protein than rC5a alone. The C5a-induced mRNA
half-life was the same as that induced by LPS. Formyl-Meth-Leu-Phe (fMLP)
did not induce cytokine transcription. Pretreatment with rC5a enhanced
cytokine synthesis induced by other stimuli. After 2 hours of preincubation
with rC5a, PBMC synthesized 3 to 10 times more IL-1 beta and TNF on
subsequent stimulation by LPS or IL-1 itself. We conclude that rC5a
provides primarily a transcriptional but not translational signal for IL-1
beta and TNF; the half-life of the untranslated mRNA is the same as that of
translated message; rC5a-induced transcription upregulates PBMC for
enhanced synthesis of these cytokines; and a translational signal can be
provided by LPS or IL-1 itself.
Volume 76,
Issue 8,
pp. 1631-1638,
10/15/1990
Copyright © 1990 by The American Society of Hematology
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