Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop.
Mucus hypersecretion and persistent airway inflammation are common features of various airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. One key question is: does the associated airway inflammation in these diseases affect mucus production? If so, what is the underlying mechanism? It appears that increased mucus secretion results from increased mucin gene expression and is also frequently accompanied by an increased number of mucous cells (goblet cell hyperplasia/metaplasia) in the airway epithelium. Many studies on mucin gene expression have been directed toward Th2 cytokines such as interleukin (IL)-4, IL-9, and IL-13 because of their known pathophysiological role in allergic airway diseases such as asthma. However, the effect of these cytokines has not been definitely linked to their direct interaction with airway epithelial cells. In our study, we treated highly differentiated cultures of primary human tracheobronchial epithelial (TBE) cells with a panel of cytokines (interleukin-1alpha, 1beta, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, and tumor necrosis factor alpha). We found that IL-6 and IL-17 could stimulate the mucin genes, MUC5B and MUC5AC. The Th2 cytokines IL-4, IL-9, and IL-13 did not stimulate MUC5AC or MUC5B in our experiments. A similar stimulation of MUC5B/Muc5b expression by IL-6 and IL-17 was demonstrated in primary monkey and mouse TBE cells. Further investigation of MUC5B expression demonstrated that IL-17's effect is at least partly mediated through IL-6 by a JAK2-dependent autocrine/paracrine loop. Finally, evidence is presented to show that both IL-6 and IL-17 mediate MUC5B expression through the ERK signaling pathway.
Chen
Yin
Y
Center for Comparative Respiratory Biology and Medicine, University of California, Davis, California 95616, USA.
Thai
Philip
P
Zhao
Yu-Hua
YH
Ho
Ye-Shih
YS
DeSouza
Mary M
MM
Wu
Reen
R
D000818:Animals; D019898:Autocrine Communication; D005786:Gene Expression Regulation / Q000187:drug effects*; D000882:Haplorhini; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics; D019899:Paracrine Communication; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000502:physiology
D020381:Interleukin-17; D015850:Interleukin-6; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins