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IL-6 Protects against Hyperoxia-Induced Mitochondrial Damage via Bcl-2–Induced Bak Interactions with Mitofusions

¹ Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Aaron B. Waxman, M.D., Ph.D., Pulmonary Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Bulfinch 148, Boston, MA 02114. E-mail: abwaxman{at}partners.org

Overexpression of IL-6 markedly diminishes hyperoxic lung injury, hyperoxia-induced cell death, and DNA fragmentation, and enhances Bcl-2 expression. We hypothesized that changes in the interactions between Bcl-2 family members play an important role in the IL-6–mediated protective response to oxidative stress. Consistent with this hypothesis, we found that IL-6 induced Bcl-2 expression, both in vivo and in vitro, disrupted interactions between proapoptotic and antiapoptotic factors, and suppressed H₂O₂-induced loss of mitochondrial membrane potential in vitro. In addition, IL-6 overexpression in mice protects against hyperoxia-induced lung mitochondrial damage. The overexpression of Bcl-2 in vivo prolonged the survival of mice exposed to hyperoxia and inhibited alveolar capillary protein leakage. In addition, apoptosis-associated DNA fragmentation was substantially reduced in these animals. This IL-6–mediated protection was lost when Bcl-2 was silenced, demonstrating that Bcl-2 is an essential mediator of IL-6 cytoprotection. Finally, Bcl-2 blocked the dissociation of Bak from mitofusion protein (Mfn) 2, and inhibited the interaction between Bak and Mfn1. Taken together, our results suggest that IL-6 induces Bcl-2 expression to perform cytoprotective functions in response to oxygen toxicity, and that this effect is mediated by alterations in the interactions between Bak and Mfns.

Key Words: lung injury • mitochondria • apoptosis • cytochrome c • Bax

CLINICAL RELEVANCE Our study shows that IL-6 regulates mitochondrial fusion interactions with the proapoptotic protein Bak. Our data suggest that IL-6–induced increases in Bcl-2 regulate Bak interactions with mitofusions and Bcl-2 inhibits Bak dissociation from mitofusion protein (Mfn) 2. In addition, Bcl-2 inhibits Bak interaction with Mfn1. In this way, IL-6–induced Bcl-2 inhibits hyperoxia-induced cell death and imparts improved survival in IL-6–transgenic animals.