Adenosine up-regulation of the mucin gene, MUC2, in asthma.
Mucus hypersecretion is a hallmark of asthma that contributes to airway obstruction. While the etiology is not well understood, hypersecretion has been linked to the presence of cytokines such as IL-4, IL-5, IL-9, and IL-13 in the inflamed airway. The presence of adenosine has also been noted in asthmatic airways, and adenosine-mediated signaling in mast cells has been implicated in the severe bronchoconstriction and inflammation prevalent in these patients (1, 2). Here we examine the possibility that adenosine also contributes to mucus hypersecretion by airway epithelial cells. Results in cultured airway epithelial cells showed that MUC2 mucin expression increased in response to adenosine. This appeared to be mediated by a pathway initiated at the adenosine A1 receptor that transduced signals through a Ca2+-activated Cl- channel and EGFR. That this signaling cascade is relevant to asthmatic hypersecretion was indicated by results showing that mucin induction by asthmatic tracheal aspirates was reduced by A1, CLCA1, and EGFR inhibitors. These results suggest that adenosine cooperates with inflammatory cytokines to stimulate mucin production in the asthmatic airway and supports the use of A1, CLCA1, and EGFR inhibitors in the treatment of asthma.
McNamara
Nancy
N
Biomedical Sciences Program, Cardiovascular Research Institute and Department of Anatomy, University of California San Francisco, San Francisco, California 94143-0452, USA.
Gallup
Marianne
M
Khong
Amy
A
Sucher
Anatol
A
Maltseva
Inna
I
Fahy
John
J
Basbaum
Carol
C
D000241:Adenosine / Q000494:pharmacology / Q000502:physiology*; D001249:Asthma / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors; D055262:Mucin-2; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics; D009544:Niflumic Acid / Q000494:pharmacology; D010766:Phosphorylation; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism; D014132:Trachea / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation
D007473:Ion Channels; C524625:MUC2 protein, human; D055262:Mucin-2; D009077:Mucins; D018047:Receptors, Purinergic P1; D009544:Niflumic Acid; D066246:ErbB Receptors; D000241:Adenosine