Arachidonic acid mediates interleukin-1 and tumor necrosis factor-α- induced activation of the c-jun amino-terminal kinases in stromal cells

Maria Teresa Rizzo, Carmelo Carlo-Stella

Research output: Contribution to journalArticlepeer-review


We have previously shown that arachidonic acid mediates interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α)-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-α. 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- eicosatetraynoic 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-α in the activation of c-jun.

Original languageEnglish
Pages (from-to)3792-3800
Number of pages9
Issue number10
Publication statusPublished - Nov 15 1996

ASJC Scopus subject areas

  • Hematology


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