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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2503-2510
Interleukin-4 and -13 Induce Upregulation of the Murine Macrophage
12/15-Lipoxygenase Activity: Evidence for the Involvement of
Transcription Factor STAT6
Dagmar Heydeck,
Leo Thomas,
Kerstin Schnurr,
Frank Trebus,
William
E. Thierfelder,
James N. Ihle, and
Hartmut Kühn
From the Institute of Biochemistry, University Clinics Charité,
Humboldt University, Berlin; the Department of Cardiovascular/
Metabolic Research, Boehringer Ingelheim Pharma KG, Biberach, Germany;
and the Department of Biochemistry, St Jude Children's Research
Hospital, Memphis, TN.
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.
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