Sphingosine kinase 1 regulates mucin production via ERK phosphorylation.
Our previous report showed that inhibition of sphingosine kinase (SphK) ameliorates eosinophilic inflammation and mucin production in a mouse asthmatic model. To clarify the role of SphK in airway mucin production, we utilized the mouse asthmatic model and found that both SphK and MUC5AC expression were increased and co-localized in airway epithelium. Next we cultured normal human bronchial epithelial cells in an air-liquid interface and treated with IL-13 to induce their differentiation into goblet cells. We found that SphK1 and MUC5AC expression was increased by IL-13 treatment at both protein and mRNA levels, whereas SphK2 expression was not changed. N,N-dimethylsphingosine (DMS), a potent SphK inhibitor, decreased MUC5AC expression up-regulated by IL-13 treatment. Furthermore, DMS inhibited IL-13-induced ERK1/2 phosphorylation but neither p38 MAPK nor STAT6 phosphorylation. These results suggest that SphK1 is involved in MUC5AC production induced by IL-13 upstream of ERK1/2 phosphorylation, and independent of STAT6 phosphorylation.
Kono
Yuko
Y
The Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Nishiuma
Teruaki
T
Okada
Taro
T
Kobayashi
Kazuyuki
K
Funada
Yasuhiro
Y
Kotani
Yoshikazu
Y
Jahangeer
Saleem
S
Nakamura
Shun-Ichi
S
Nishimura
Yoshihiro
Y
D000818:Animals; D001249:Asthma / Q000201:enzymology; D001980:Bronchi / Q000201:enzymology; D018793:Interleukin-13 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D055271:Mucin 5AC / Q000096:biosynthesis*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000099157:Sphingosine Kinase
D018793:Interleukin-13; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D055271:Mucin 5AC; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C524679:Muc5ac protein, mouse; C061800:N,N-dimethylsphingosine