Interleukin-1 beta and tumor necrosis factor-alpha induce MUC5AC overexpression through a mechanism involving ERK/p38 mitogen-activated protein kinases-MSK1-CREB activation in human airway epithelial cells.
Mucin hypersecretion is commonly observed in many inflammatory diseases of the respiratory tract. MUC5AC is generally recognized to be a major airway mucin because MUC5AC is highly expressed in the goblet cells of human airway epithelium. Moreover, it is regulated by various inflammatory cytokines. However, the mechanisms by which the interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha induce MUC5AC gene expression in normal nasal epithelial cells, and the signal molecules involved, especially in the downstream signaling of mitogen-activated protein (MAP) kinases, remain unclear. Here we show that pharmacologic or genetic inhibition of either ERK or p38 MAP kinase pathway abolished IL-1beta- and TNF-alpha-induced MUC5AC gene expression in normal human nasal epithelial cells. Our results also indicate that the activation of mitogen- and stress-activated protein kinase 1 (MSK1) and cAMP-response element-binding protein and cAMP-response element signaling cascades via ERK and p38 MAP kinases are crucial aspects of the intracellular mechanisms that mediate MUC5AC gene expression. Taken together, these studies give additional insights into the molecular mechanism of IL-1beta- and TNF-alpha-induced MUC5AC gene expression and enhance our understanding on mucin hypersecretion during inflammation.
Song
Kyoung Seob
KS
Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea.
Lee
Won-Jae
WJ
Chung
Kwang Chul
KC
Koo
Ja Seok
JS
Yang
Eun Jin
EJ
Choi
Jae Young
JY
Yoon
Joo-Heon
JH
D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D055271:Mucin 5AC; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009297:Nasal Mucosa / Q000166:cytology / Q000378:metabolism*; D020218:Response Elements; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D017362:Cyclic AMP Response Element-Binding Protein; D007375:Interleukin-1; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D014409:Tumor Necrosis Factor-alpha; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases