Interleukin-4 and -13 induce upregulation 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 presence of interleukin (IL)-4 or IL-13, the expression of the reticulocyte-type 15-lipoxygenase is induced. In mice a 15-lipoxygenase is not expressed, 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 peritoneal macrophages by interleukins and found that the activity of this enzyme is upregulated in a dose-dependent manner when the cells were cultured in the presence of the IL-4 or IL-13 but not by IL-10. When peripheral murine monocytes that do not express the lipoxygenase were treated with IL-4 expression of 12/15-lipoxygenase mRNA was induced, suggesting pretranslational control mechanisms. In contrast, no upregulation 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 threefold to fourfold higher 12-lipoxygenase activity than cells prepared from control animals. A similar upregulation of 12-lipoxygenase activity 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 that (1) the 12-lipoxygenase activity of murine macrophages is upregulated in vitro and in vivo by IL-4 and/or IL-13, (2) this upregulation requires expression of the transcription factor STAT6, and (3) the constitutive expression of the enzyme appears to be STAT6 independent. The cytokine-dependent upregulation of the murine macrophage 12-lipoxygenase and its induction during experimental anemia suggests its close relatedness with the human reticulocyte-type 15-lipoxygenase despite their differences in the positional specificity of arachidonic acid oxygenation.
Heydeck
D
D
Institute of Biochemistry, University Clinics Charité, Humboldt University, Berlin.
Thomas
L
L
Schnurr
K
K
Trebus
F
F
Thierfelder
W E
WE
Ihle
J N
JN
Kühn
H
H
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000096:biosynthesis; D000740:Anemia / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D016753:Interleukin-10 / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D013268:Stimulation, Chemical; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D006893:Hydroxyeicosatetraenoic Acids; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D016753:Interleukin-10; D015847:Interleukin-4; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase