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Leukotriene B4 enhances interleukin-6 (IL-6) production and IL-6 messenger
RNA accumulation in human monocytes in vitro: transcriptional and
posttranscriptional mechanisms
M Rola-Pleszczynski and J Stankova
Immunology Division, Faculty of Medicine, University of Sherbrooke, Quebec,
Canada.
Leukotriene B4 (LTB4) is a potent lipid mediator of inflammation, and some
of its bioactivities may involve inflammatory cytokines. Moreover, it may
participate in myelopoiesis, either directly or via the induction of
cytokines and growth factors. When human monocytes were cultured in the
presence of graded concentrations of LTB4, significant stimulation of
production of bioactive and immunoreactive interleukin-6 (IL-6) was
observed. Nanomolar concentrations of LTB4 were optimal and the LTB4
receptor antagonist LY 255283 could block its activity. The omega-oxidation
products of LTB4, 20-OH-LTB4 and 20-COOH-LTB4, were only 22% and 2%
effective, respectively. LTA4 was also effective in stimulating IL-6
production, but only at micromolar concentrations, whereas 5-HETE and
12-epi-LTB4 were ineffective. The signaling induced by LTB4 did not seem to
involve protein kinase C or A, but rather a tyrosine kinase, as suggested
by its inhibition with genistein. LTB4 induced an accumulation of IL-6
messenger RNA (mRNA) in treated monocytes with a dose-response similar to
that of IL-6 protein production. Whereas IL-6 mRNA half-life in untreated
cells was approximately 1 hour, it was extended to 3 hours in LTB4-treated
monocytes. Moreover, nuclear transcription of IL-6 mRNA was augmented at 30
minutes by a factor of 5 in LTB4-treated cells. Pretreatment of cells with
cyclohexamide before exposure to LTB4 superinduced IL-6 message expression,
but partially inhibited the effect of LTB4 on IL-6 mRNA accumulation,
suggesting that newly synthesized proteins may be involved in the
transcriptional activation of the IL-6 gene by LTB4. These findings
constitute a first demonstration that LTB4 stimulates IL- 6 production and
that the underlying mechanisms involve both increased IL-6 gene
transcription and message stabilization. This may constitute an important
mechanism through which rapidly produced mediators may modulate the
subsequent production of regulatory or growth-promoting cytokines.
Volume 80,
Issue 4,
pp. 1004-1011,
08/15/1992
Copyright © 1992 by The American Society of Hematology
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