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J. Biol. Chem., Vol. 281, Issue 7, 4231-4241, February 17, 2006
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Up-regulation of AMP-activated Kinase by Dysfunctional Cystic Fibrosis Transmembrane Conductance Regulator in Cystic Fibrosis Airway Epithelial Cells Mitigates Excessive Inflammation*
1
From the
Departments of Medicine and Pediatrics and ¶Center for Environmental and Occupational Health, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, the Departments of Medicine and Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, the ||Departments of Pediatrics and Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35233, and the **Department of Medicine, Indiana University, Indianapolis, Indiana 46202
AMP-activated kinase (AMPK) is a ubiquitous metabolic sensor that inhibits the cystic fibrosis (CF) transmembrane conductance regulator (CFTR). To determine whether CFTR reciprocally regulates AMPK function in airway epithelia and whether such regulation is involved in lung inflammation, AMPK localization, expression, and activity and cellular metabolic profiles were compared as a function of CFTR status in CF and non-CF primary human bronchial epithelial (HBE) cells. As compared with non-CF HBE cells, CF cells had greater and more diffuse AMPK staining and had greater AMPK activity than their morphologically matched non-CF counterparts. The cellular [AMP]/[ATP] ratio was higher in undifferentiated than in differentiated non-CF cells, which correlated with AMPK activity under these conditions. However, this nucleotide ratio did not predict AMPK activity in differentiating CF cells. Inhibiting channel activity in non-CF cells did not affect AMPK activity or metabolic status, but expressing functional CFTR in CF cells reduced AMPK activity without affecting cellular [AMP]/[ATP]. Therefore, lack of functional CFTR expression and not loss of channel activity in CF cells appears to up-regulate AMPK activity in CF HBE cells, presumably through non-metabolic effects on upstream regulatory pathways. Compared with wild-type CFTR-expressing immortalized CF bronchial epithelial (CFBE) cells, 
F508-CFTR-expressing CFBE cells had greater AMPK activity and greater secretion of tumor necrosis factor-
and the interleukins IL-6 and IL-8. Further pharmacologic AMPK activation inhibited inflammatory mediator secretion in both wild type- and F508-expressing cells, suggesting that AMPK activation in CF airway cells is an adaptive response that reduces inflammation. We propose that therapies to activate AMPK in the CF airway may be beneficial in reducing excessive airway inflammation, a major cause of CF morbidity.
Received for publication, October 11, 2005 , and in revised form, December 16, 2005.
* This work was supported by National Institutes of Health Grants K08-DK059477 (to K. R. H.), P30-DK072506 (to K. R. H., J. K. K., and J. M. P.), R01-HL067088 (to J. P. C.), R01-DK060495 (to P. D.), R01-DK035712 (to L. A. W.) and by the Cystic Fibrosis Foundation (to J. P. C. and J. M. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Dept. of Medicine, University of Pittsburgh, S976 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: 412-648-9580; Fax: 412-383-8956; E-mail: hallows{at}pitt.edu.
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