INTERLEUKIN-4-MEDIATED INHIBITION OF C-FOS MESSENGER-RNA 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 protooncogene mRNA express ion. 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 se lectively inhibit the cyclooxygenase dependent (indomethacin) and lipo xygenase dependent (NDGA) pathway of arachidonic acid (AA) metabolism. NDGA inhibited A23187-induced c-fos mRNA expression by a similar magn itude as IL-4, whereas the effect of indomethacin was only minor. A231 87-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 l ipoxygenase directed pathway of AA metabolism, whereas the cyclooxygen ase dependent pathway is not involved in the regulation of proto-oncog ene expression. This was supported by the finding that leukotriene B4 (LTB4) and 5'-hydroperoxy-eicosatetraenoic acid (5'-HPTETE), which are two lipoxygenase metabolites, strongly induced c-fos mRNA, whereas c- jun mRNA expression was slightly affected. However, the inhibitive eff ect of IL-4 could not be ascribed to a reduced production of LTB4 sugg esting that the mode of IL-4 action lies behind the conversion of AA t o 5'-HPETE and LTB4.