Regulation of Retinoic Acid Receptor Beta by Interleukin-15 in the Lung during Cigarette Smoking and Influenza Virus Infection.
Virus-induced exacerbations often lead to further impairment of lung function in chronic obstructive pulmonary disease. IL-15 is critical in antiviral immune responses. Retinoic acid (RA) signaling plays an important role in tissue maintenance and repair, particularly in the lung. We studied RA signaling and its relation to IL-15 in the lung during cigarette smoke (CS) exposure and influenza virus infection. In vivo studies show that RA signaling is diminished by long-term CS exposure or influenza virus infection alone, which is further attenuated during infection after CS exposure. RA receptor β (RARβ) is specifically decreased in the lung of IL-15 transgenic (overexpression; IL-15Tg) mice, and a greater reduction in RARβ is found in these mice compared with wild-type (WT) mice after infection. RARβ is increased in IL-15 knockout (IL-15KO) mice compared with WT mice after infection, and the additive effect of CS and virus on RARβ down-regulation is diminished in IL-15KO mice. IL-15 receptor α (IL-15Rα) is increased and RARβ is significantly decreased in lung interstitial macrophages from IL-15Tg mice compared with WT mice. In vitro studies show that IL-15 down-regulates RARβ in macrophages via IL-15Rα signaling during influenza virus infection. These studies suggest that RA signaling is significantly diminished in the lung by CS exposure and influenza virus infection. IL-15 specifically down-regulates RARβ expression, and RARβ may play a protective role in lung injury caused by CS exposure and viral infections.
1 Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.|2 Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and.
Jianmiao
J
Wang
1 Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.
Wei
W
Liu
1 Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.
Chad
C
Marion
1 Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.
Rajvir
R
Singh
1 Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.
Nathaniel
N
Andrews
3 Medicine and Biologic Sciences, Brown University, Warren Alpert Medical School, Providence, Rhode Island.
Chun Geun
CG
Lee
3 Medicine and Biologic Sciences, Brown University, Warren Alpert Medical School, Providence, Rhode Island.
Jack A
JA
Elias
1 Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.
Charles S
http://orcid.org/0000-0002-5258-1797
CS
Dela Cruz
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D007251:Influenza, Human / Q000276:immunology / Q000378:metabolism*; D019409:Interleukin-15 / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053647:Receptors, Interleukin-15 / Q000378:metabolism; D049230:Retinoid X Receptor beta / Q000235:genetics / Q000378:metabolism*; D047491:Retinoid X Receptor gamma / Q000235:genetics / Q000378:metabolism*; D012907:Smoking / Q000276:immunology / Q000378:metabolism*
D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D049230:Retinoid X Receptor beta; D047491:Retinoid X Receptor gamma
IL-15; chronic obstructive pulmonary disease; cigarette smoke; influenza; retinoic acid receptor