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Transcription Factor1
Eicosanoid and Lipid Research Division, Department of Gynecology, University Medical Center Benjamin Franklin, Free University Berlin, Berlin, Germany
The proinflammatory cytokine IL-4 is secreted in large amounts
during allergic inflammatory response in asthma and plays a pivotal
role in the airway inflammation. IL-4 has been shown to up-regulate
15-lipoxygenase and produce
15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549
cells via the Janus kinase/STAT6 pathway under coactivation of CREB
binding protein/p300. IL-4 has also been shown to up-regulate
peroxisome proliferator-activated receptor 
(PPAR) nuclear
receptors in macrophages and A549 cells. In this study we demonstrate
that 15(S)-HETE binds to PPAR nuclear receptors and induces
apoptosis in A549 cells. Moreover, pretreatment of cells with
nordihydroguaiaretic acid, a 15-lipoxygenase inhibitor, prevented
PPAR activation and apoptosis. The latter was accomplished by the
interaction of the 15(S)-HETE/PPAR complex with the adapter protein
Fas-associating protein with death domain and caspase-8, as shown by
transfection of Fas-associating protein with death domain dominant
negative vector and cleavage of caspase 8 to active subunits p41/42 and
p18. Whereas IL-4 and PPAR ligands failed to induce cleavage of Bid
and release of cytochrome c from mitochondria, they
caused translocation of the proapoptotic protein Bax from cytoplasm to
mitochondria with a concomitant decrease in the Bcl-xL
level. We therefore believe that in unstimulated cells
Bcl-xL and Bax form a heterodimer, in which
Bcl-xL dominates and prevents the induction of apoptosis,
whereas in IL-4-stimulated cells the 15(S)-HETE/PPAR complex
down-regulates Bcl-xL, and the resulting overweight of Bax
commits the cell to apoptosis via caspase-3. However, this pathway does
not rule out the direct caspase-8-mediated activation of caspase-3. In
conclusion, IL-4-induced apoptosis may contribute to severe loss of
alveolar structures and infiltration of eosinophils, mononuclear
phagocytes, etc., into the lung tissue of chronic asthma
patients.
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