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STAT3 Regulates ABCA3 Expression and Influences Lamellar Body Formation in Alveolar Type II Cells

¹ Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to Jeffrey A. Whitsett, M.D., Cincinnati Children's Hospital Medical Center, Section of Neonatology, Perinatal and Pulmonary Biology, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. E-mail: jeff.whitsett{at}cchmc.org

ATP-Binding Cassette A3 (ABCA3) is a lamellar body associated lipid transport protein required for normal synthesis and storage of pulmonary surfactant in type II cells in the alveoli. In this study, we demonstrate that STAT3, activated by IL-6, regulates ABCA3 expression in vivo and in vitro. ABCA3 mRNA and immunostaining were decreased in adult mouse lungs in which STAT3 was deleted from the respiratory epithelium (Stat3^/ mice). Consistent with the role of STAT3, intratracheal IL-6 induced ABCA3 expression in vivo. Decreased ABCA3 and abnormalities in the formation of lamellar bodies, the intracellular site of surfactant lipid storage, were observed in Stat3^/ mice. Expression of SREBP1a and 1c, SCAP, ABCA3, and AKT mRNAs was inhibited by deletion of Stat3 in type II cells isolated from Stat3^/ mice. The activities of PI3K and AKT were required for normal Abca3 gene expression in vitro. AKT activation induced SREBP expression and increased the activity of the Abca3 promoter in vitro, consistent with the role of STAT3 signaling, at least in part via SREBP, in the regulation of ABCA3. ABCA3 expression is regulated by IL-6 in a pathway that includes STAT3, PI3K, AKT, SCAP, and SREBP. Activation of STAT3 after exposure to IL-6 enhances ABCA3 expression, which, in turn, influences pulmonary surfactant homeostasis.

Key Words: STAT3 • ABCA3 • IL-6 • gene regulation • surfactant • hyperoxia

CLINICAL RELEVANCE This work provides a mechanism by which activation of IL-6/STAT3 regulates ABCA3 in type II cells in the alveoli. ABCA3 is required for lamellar body formation and surfactant homeostasis that maintains lung function at birth and after injury.