Leptin enhances ICAM-1 expression, induces migration and cytokine synthesis, and prolongs survival of human airway epithelial cells.
There is rising interest in how obesity affects respiratory diseases, since epidemiological findings indicate a strong relationship between the two conditions. Leptin is a potent adipokine produced mainly by adipocytes. It regulates energy storage and expenditure and also induces inflammation. Previous studies have shown that leptin is able to activate inflammatory cells such as lymphocytes and granulocytes, but little is known about its effect on lung structural cells. The present study investigated the effects of leptin on human airway epithelial cells by using human primary airway epithelial cells and a human airway epithelial cell line, BEAS-2B. Flow cytometry showed enhanced ICAM-1 expression by both of those cells in response to leptin, and that effect was abrogated by dexamethasone or NF-κB inhibitor. Flow cytometry and quantitative PCR showed that airway epithelial cells expressed leptin receptor (Ob-R), whose expression level was downregulated by leptin itself. Multiplex cytokine analysis demonstrated enhanced production of CCL11, G-CSF, VEGF, and IL-6 by BEAS-2B cells stimulated with leptin. Furthermore, transfection of Ob-R small interference RNA decreased the effect of leptin on CCL11 production as assessed by quantitative PCR. Finally, leptin induced migration of primary airway epithelial cells toward leptin, suppressed BEAS-2B apoptosis induced with TNF-α and IFN-γ, and enhanced proliferation of primary airway epithelial cells. In summary, leptin was able to directly activate human airway epithelial cells by binding to Ob-R and by NF-κB activation, resulting in upregulation of ICAM-1 expression, induction of CCL11, VEGF, G-CSF, and IL-6 synthesis, induction of migration, inhibition of apoptosis, and enhancement of proliferation.
National Hospital Organization Tokyo National Hospital, Tokyo, Japan; fueta-tky@umin.ac.jp.
Maho
M
Suzukawa
Nishikobe Medical Center, Kobe, Japan;
Rikiya
R
Koketsu
Department of Otolaryngology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan;
Shintaro
S
Baba
National Hospital Organization Tokyo National Hospital, Tokyo, Japan;
Sayaka
S
Igarashi
Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan; and.
Hiroyuki
H
Nagase
Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan; and.
Masao
M
Yamaguchi
Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.
Noriyuki
N
Matsutani
Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.
Masafumi
M
Kawamura
National Hospital Organization Tokyo National Hospital, Tokyo, Japan;
Shunsuke
S
Shoji
National Hospital Organization Tokyo National Hospital, Tokyo, Japan;
Akira
A
Hebisawa
National Hospital Organization Tokyo National Hospital, Tokyo, Japan;
Ken
K
Ohta
D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D054413:Chemokine CCL11 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D055785:Gene Knockdown Techniques; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D020738:Leptin / Q000494:pharmacology / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D020545:Respiratory Mucosa / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
C515456:CCL11 protein, human; D054413:Chemokine CCL11; D016207:Cytokines; C508600:IL6 protein, human; D015850:Interleukin-6; C515448:LEPR protein, human; D020738:Leptin; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054411:Receptors, Leptin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor
Ob-R; airway epithelial cells; asthma; human; leptin