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This version published online on March 25, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0458
Molecular Endocrinology Vol. 0, No. 2004 200304581-
doi:10.1210/me.2003-0458
Copyright © 2004 by the Endocrine Society.
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Submitted on November 27, 2003
Accepted on March 17, 2004

Synergy between Stat3 and RAR{alpha} in Regulation of the Surfactant Protein B Gene in the Lung

Li Yang, Xuemei Lian, Angelynn Cowen, Huan Xu, Hong Du, and Cong Yan*

Division of Pulmonary Biology, Division of Human Genetics and The Graduate Program for Molecular and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039. The Graduate Program for Pediatrics, Chongqing University of Medical Sciences, Chongqing, China, 400016.

* To whom correspondence should be addressed. E-mail: Cong.Yan{at}cchmc.org.

During respiratory cycles, airborne particles and pathogens are inhaled into the lung, which can cause cytokine production by respiratory macrophages and inflammatory responses. Secreted cytokines affect surfactant protein expression and homeostasis in the lung. In co-culturing experiment in vitro, broncho-alveolar macrophages stimulated human surfactant protein B (hSP-B) gene transcription in primary alveolar type II (AT II) epithelial cells in lipopolysaccharide (LPS) independent and dependent ways. Neutralization by interleukin 6 (IL-6) antibody abolished LPS dependent macrophage stimulation of hSP-B gene transcription. IL-6 treatment enhanced Stat3 phosphorylation at Y705 in AT II epithelial cells and Clara cells in vivo. Biochemical analysis of functional domain swapping between Stat1 and Stat3 identified that the SH2 domain and the DNA binding domain are critical for Stat3 stimulation of hSP-B gene transcription. GST-pull down study determined functional domains required for protein-protein interaction between Stat3 and RAR{alpha}. Co-transfection of Stat3 and RAR{alpha} into respiratory epithelial cells resulted in synergistic DNA-binding and transcriptional activation on the hSP-B gene. To assess Stat3 physiological function, overexpression of a dominant negative Stat3 in respiratory epithelial cells in a doxycycline-controlled double transgenic mouse line caused pulmonary emphysema and increase of animal death during hyperoxia. Therefore, the IL-6/Stat3 signaling axis plays an important role in surfactant protein homeostasis and respiratory inflammation in the lung.
Key words: IL-6 • Stat3 • RAR • Surfactant protein B • emphysema • oxygen injury

NURSA Molecule Pages Link:

Nuclear Receptors:   RARα  |  RXRα



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