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Arachidonic acid mediates interleukin-1 and tumor necrosis factor-alpha-
induced activation of the c-jun amino-terminal kinases in stromal cells
MT Rizzo and C Carlo-Stella
Bone Marrow Transplantation Laboratory, Methodist Cancer Center, Methodist
Hospital, Indianapolis, IN 46202, USA.
We have previously shown that arachidonic acid mediates interleukin-1
(IL-1) and tumor necrosis factor-alpha (TNF-alpha)-induced transcription of
c-jun. The signaling pathway of arachidonic acid- induced c-jun
transcription was independent of protein kinase C activation and involved a
tyrosine kinase-dependent process. The present study was undertaken to
further elucidate the signal transduction pathway of arachidonate-induced
c-jun transcription. We used a glutathione-S-transferase-c-jun fusion
protein containing the aminoterminal domain of c-jun (residues 5 to 89) to
explore the hypothesis that arachidonic acid stimulates c-jun
amino-terminal kinase (JNK) activity in the murine stromal cell line +/+.1
LDA 11. Extracts from arachidonic acid-treated cells catalyzed
phosphorylation of the c- jun fusion protein, indicating stimulation of JNK
activity. Similar results were obtained when cells were challenged with
IL-1 and TNF- alpha. The effect of arachidonic acid was specific, because
extracts from stimulated cells failed to phosphorylate a mutated fusion
protein in which serine 63 and 73 of c-jun were each substituted with
leucine. Arachidonic acid induced JNK activation in a time- and
dose-dependent manner that was not mimicked by saturated fatty acids such
as palmitic acid or other unsaturated fatty acids from the n-3, n-6, or n-9
series. Furthermore, other lipids, such as diacylglycerol, phosphatidic
acid, and C2-ceramide, failed to induce a significant increase in JNK
activity. Treatment of stromal cells with propyl gallate, a dual inhibitor
of lipoxygenase and cyclooxygenase enzymes, did not affect the ability of
arachidonic acid to induce JNK activation. Moreover, ETYA
(5,8,11,14-eicosate-traynoic acid), a nonmetabolizable arachidonate
analogue, also induced JNK activation. These results are consistent with
the hypothesis that the signal transduction pathway by which arachidonate
stimulates c-jun transcription involves activation of the JNK cascade.
Furthermore, arachidonic acid itself and not its cyclooxygenase or
lipoxygenase metabolites is involved in stimulating JNK activity. Thus,
arachidonic acid may act as a second messenger in mediating the effects of
IL-1 and TNF-alpha in the activation of c-jun.
Volume 88,
Issue 10,
pp. 3792-3800,
11/15/1996
Copyright © 1996 by The American Society of Hematology

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