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*Lung Cancer
The Journal of Immunology, 2003, 170: 887-894.
Copyright © 2003 by The American Association of Immunologists

IL-4 Induces Apoptosis in A549 Lung Adenocarcinoma Cells: Evidence for the Pivotal Role of 15-Hydroxyeicosatetraenoic Acid Binding to Activated Peroxisome Proliferator-Activated Receptor {gamma} Transcription Factor1

Pattabhiraman Shankaranarayanan and Santosh Nigam2

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 {gamma} (PPAR{gamma}) nuclear receptors in macrophages and A549 cells. In this study we demonstrate that 15(S)-HETE binds to PPAR{gamma} nuclear receptors and induces apoptosis in A549 cells. Moreover, pretreatment of cells with nordihydroguaiaretic acid, a 15-lipoxygenase inhibitor, prevented PPAR{gamma} activation and apoptosis. The latter was accomplished by the interaction of the 15(S)-HETE/PPAR{gamma} 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{gamma} 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{gamma} 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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