Role of arachidonic acid metabolism in transcriptional induction of tumor necrosis factor gene expression by phorbol ester.

Abstract

The treatment of human HL-60 promyelocytic leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with induction of tumor necrosis factor (TNF) transcripts. The study reported here has examined TPA-induced signaling mechanisms responsible for the regulation of TNF gene expression in these cells. Run-on assays demonstrated that TPA increases TNF mRNA levels by transcriptional activation of this gene. The induction of TNF transcripts by TPA was inhibited by the isoquinolinesulfonamide derivative H7 but not by HA1004, suggesting that this effect of TPA is mediated by activation of protein kinase C. TPA treatment also resulted in increased arachidonic acid release. Moreover, inhibitors of phospholipase A2 blocked both the increase in arachidonic acid release and the induction of TNF transcripts. These findings suggest that TPA induces TNF gene expression through the formation of arachidonic acid metabolites. Although indomethacin had no detectable effect on this induction of TNF transcripts, ketoconazole, an inhibitor of 5-lipoxygenase, blocked TPA-induced increases in TNF mRNA levels. Moreover, TNF mRNA levels were increased by the 5-lipoxygenase metabolite leukotriene B4. In contrast, the cyclooxygenase metabolite prostaglandin E2 inhibited the induction of TNF transcripts by TPA. Taken together, these results suggest that TPA induces TNF gene expression through the arachidonic acid cascade and that the level of TNF transcripts is regulated by metabolites of the pathway, leukotriene B4 and prostaglandin E2.

Regulation of tumor necrosis factor gene expression by ionizing radiation in human myeloid leukemia cells and peripheral blood monocytes.

“…Furthermore, preincubation with TPA to downregulate protein kinase C also abolished the response of x rays (34). Together with the results demonstrating the induction of TNF gene expression by phorbol esters (20,28), these findings suggest that the effects of ionizing radiation on TNF gene expression might also be mediated by a protein kinase C-dependent mechanism.…”

“…TNF is actively transcribed in thioglycollate-elicited peritoneal macrophages, while an increase in the rate of TNF transcription was observed after treatment with LPS or interferon-y (26,27). We have previously demonstrated that TNF induction by 12-tetradecanoylphorbol-13-acetate (TPA)' is regulated by transcriptional mechanisms in human peripheral blood monocytes as well as in myeloid leukemia cell lines (20,28). In order to determine the level of regulation ofTNF gene expression by ionizing radiation, we first measured the rate ofTNF transcription in isolated nuclei using the run-on transcription assay method.…”

Expression of the early growth response 1 and 2 zinc finger genes during induction of monocytic differentiation.

“…Taken together, these results indicated that M-CSF regulates EGR-I gene expression in monocytes by both transcriptional and posttranscriptional mechanisms, whereas EGR-2 expression is regulated at least in part by a posttranscriptional mechanism in these cells. We have previously demonstrated that glucocorticoids inhibit induction of monocytic differentiation (20)(21)(22). Consequently, we treated TPA-induced U-937 cells with dexamethasone to determine the effects of this agent on EGR-l gene expression.…”

“…(10)(11)(12)(13)(14)(15)(16). Previous studies have demonstrated that the c-jun, jun-B, and c-fos genes are activated during TPA-induced monocytic differentiation (7,(17)(18)(19)(20). Moreover, the finding that pretreatment with dexamethasone inhibits expression of these genes, as well as TPA-or dimethyl sulfoxide (DMSO)-induced monocytic differentiation, has implicated a role for Jun/ AP-l in this process (20)(21)(22).…”

Adenosine A2 receptor‐induced inhibition of leukotriene B4 synthesis in whole blood ex vivo

“…Furthermore, LTB4 was found to modulate the production of cytokines by monocytes (Rola-Pleszczinski & Lemaire, 1985; 'Author for correspondence. Horiguchi et al, 1989;Rola-Pleszczinski & Stankova, 1992) and the proliferation of lymphocytes (Payan et al, 1984;Gualde et al, 1985;Atluru & Goodwin, 1986;Yamaoka et al, 1989). The recent development of LTB4 antagonists and inhibitors of 5-lipoxygenase have outlined a role for this lipid mediator in acute inflammatory states such as in endotoxic shock (Matera et al, 1988;Fujimoto & Kobayashi, 1988;Coggeshall et al, 1988;Yoshikawa & Goto, 1992).…”