Interleukin-4-mediated inhibition of C-Fos mRNA expression: role of the lipoxygenase directed pathway.
Interleukin-4 inhibits several monocyte functions like A23187-induced expression of cytokines and c-fos and c-jun proto-oncogene mRNA expression. In an attempt to elucidate the mechanism by which this inhibitive effect is mediated, we compared the effect of IL-4 on A23187-induced c-fos and c-jun mRNA expression in conjunction with inhibitors that selectively inhibit the cyclooxygenase dependent (indomethacin) and lipoxygenase dependent (NDGA) pathway of arachidonic acid (AA) metabolism. NDGA inhibited A23187-induced c-fos mRNA expression by a similar magnitude as IL-4, whereas the effect of indomethacin was only minor. A23187-induced c-jun mRNA expression was not affected by indomethacin and only slightly inhibited by NDGA. These results indicate that in human monocytes c-fos mRNA expression is at least partly controlled by the lipoxygenase directed pathway of AA metabolism, whereas the cyclooxygenase dependent pathway is not involved in the regulation of proto-oncogene expression. This was supported by the finding that leukotriene B4 (LTB4) and 5'-hydroperoxyeicosatetraenoic acid (5'-HPTETE), which are two lipoxygenase metabolites, strongly induced c-fos mRNA, whereas c-jun mRNA expression was slightly affected. However, the inhibitive effect of IL-4 could not be ascribed to a reduced production of LTB4 suggesting that the mode of IL-4 action lies behind the conversion of AA to 5'-HPETE and LTB4.
Department of Medicine, University of Groningen, The Netherlands.
W H
WH
Dokter
S J
SJ
Sierdsema
M T
MT
Esselink
M R
MR
Halie
E
E
Vellenga
D016718:Arachidonic Acid / Q000378:metabolism; D000001:Calcimycin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects*; D016758:Genes, jun; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D007975:Leukotriene B4 / Q000494:pharmacology; D008084:Lipoxygenase / Q000378:metabolism* / Q000502:physiology; D010105:Oxygenases / Q000378:metabolism / Q000502:physiology; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D007975:Leukotriene B4; D015847:Interleukin-4; D016718:Arachidonic Acid; D000001:Calcimycin; D010105:Oxygenases; D008084:Lipoxygenase; D007213:Indomethacin