INTERLEUKIN-4 AND INTERLEUKIN-13 INDUCE UP-REGULATION OF THE MURINE MACROPHAGE 12 15-LIPOXYGENASE ACTIVITY - EVIDENCE FOR THE INVOLVEMENT OF TRANSCRIPTION FACTOR STAT6/

When human monocytes or alveolar macrophages are cultured in the prese nce of interleukin (IL)-4 or IL-13, the expression of the reticulocyte -type 15-lipoxygenase is induced. In mice a 15-lipoxygenase is not exp ressed, but a leukocyte-type 12-lipoxygenase is present in peritoneal macrophages, To investigate whether both lipoxygenase isoforms exhibit a similar regulatory response toward cytokine stimulation, we studied the regulation of the leukocyte-type 12-lipoxygenase of murine perito neal macrophages by interleukins and found that the activity of this e nzyme is upregulated in a dose-dependent manner when the cells were cu ltured in the presence of the IL-4 or IL-13 but not by IL-10, When per ipheral murine monocytes that do not express the lipoxygenase were tre ated with IL-4 expression of 12/15-lipoxygenase mRNA was induced, sugg esting pretranslational control mechanisms. In contrast, no upregulati on of the lipoxygenase activity was observed when the macrophages were prepared from homozygous STAT6-deficient mice. Peritoneal macrophages of transgenic mice that systemically overexpress IL-4 exhibited a thr eefold to fourfold higher 12-lipoxygenase activity than cells prepared from control animals. A similar upregulation of 12-lipoxygenase activ ity was detected in heart, spleen, and lung of the transgenic animals. Moreover, a strong induction of the enzyme was observed in red cells during experimental anemia in mice. The data presented here indicate t hat (1) the 12-lipoxygenase activity of murine macrophages is upregula ted in vitro and in vivo by IL-4 and/or IL-13, (2) this upregulation r equires expression of the transcription factor STAT6, and (3) the cons titutive expression of the enzyme appears to be STAT6 independent. The cytokine-dependent upregulation of the murine macrophage 12-lipoxygen ase and its induction during experimental anemia suggests its close re latedness with the human reticulocyte-type 15-lipoxygenase despite the ir differences in the positional specificity of arachidonic acid oxyge nation. (C) 1998 by The American Society of Hematology.