Leptin up-regulates MUC5B expression in human airway epithelial cells via mitogen-activated protein kinase pathway.
Leptin, an adipocyte-secreted hormone that regulates food intake and metabolic response, has been recently reported to increase in the serum during inflammatory airway disease associated with mucus-hypersecretion. We investigated the effects of leptin on mucin expression in human airway epithelial cells and the signaling pathways. The expression of the leptin receptor was evaluated in human nasal mucosa and NCI-H292 cells. Leptin-induced expression of major respiratory mucins in NCI-H292 cells was analyzed. Mutant leptin, which acts as a receptor antagonist, and specific inhibitors of extracellular signal-regulated kinase (ERK1/2), p38 and Janus kinase-2 (JAK2)/signal transducer and activator of transcription-3 (STAT3) were used. Leptin receptors were expressed in the nasal mucosa and NCI-H292 cells. Treatment with leptin significantly increased the expression of MUC5AC and MUC5B in NCI-H292 cells; these effects were blocked by mutant leptin. The cells activated by leptin showed increased ERK1/2, p38, and STAT3 phosphorylation. Leptin-induced MUC5B expression was blocked by the ERK1/2 and p38 pathway inhibitors, but not by the JAK2/STAT3 pathway inhibitor. Leptin might significantly contribute to the production of major gel-forming mucins by direct stimulation of airway epithelial cells and the activation of leptin receptors coupled with the activation of ERK1/2 or p38, but not the JAK2/STAT3 pathway.
Woo
Hyun-Jae
HJ
Department of Otorhinolaryngology-Head and Neck Surgery, Gumi CHA Hospital, CHA University, Gumi, Republic of Korea.
Yoo
Woo Jong
WJ
Bae
Chang Hoon
CH
Song
Si-Youn
SY
Kim
Yong-Woon
YW
Park
So-Young
SY
Kim
Yong-Dae
YD
D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055257:Mucin-5B / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C515448:LEPR protein, human; D020738:Leptin; C524578:MUC5B protein, human; D055257:Mucin-5B; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases