Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Biol. Chem. 287 (17): 14004-14011

© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Background: The molecular mechanisms underpinning how CO2 affects cell signaling and gene transcription are not well understood.

Results: The NF-{kappa}B family member RelB is cleaved and translocates to the nucleus of cells in response to elevated CO2 (hypercapnia).

Conclusion: The NF-{kappa}B signaling pathway is affected by CO2.

Significance: This study provides new molecular insight into modulation of inflammatory pathways under conditions of hypercapnia.

Hypercapnia Induces Cleavage and Nuclear Localization of RelB Protein, Giving Insight into CO2 Sensing and Signaling*Formula

Kathryn M. Oliver{ddagger}, Colin R. Lenihan{ddagger}, Ulrike Bruning{ddagger}, Alex Cheong{ddagger}§, John G. Laffey, Paul McLoughlin{ddagger}, Cormac T. Taylor{ddagger}§12, , and Eoin P. Cummins{ddagger}1

From the {ddagger}School of Medicine and Medical Science and
§Systems Biology Ireland, UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4 and
the School of Medicine, National University of Ireland, Galway, Ireland

ABSTRACT Back to Top

Abstract: Carbon dioxide (CO2) is increasingly being appreciated as an intracellular signaling molecule that affects inflammatory and immune responses. Elevated arterial CO2 (hypercapnia) is encountered in a range of clinical conditions, including chronic obstructive pulmonary disease, and as a consequence of therapeutic ventilation in acute respiratory distress syndrome. In patients suffering from this syndrome, therapeutic hypoventilation strategy designed to reduce mechanical damage to the lungs is accompanied by systemic hypercapnia and associated acidosis, which are associated with improved patient outcome. However, the molecular mechanisms underlying the beneficial effects of hypercapnia and the relative contribution of elevated CO2 or associated acidosis to this response remain poorly understood. Recently, a role for the non-canonical NF-{kappa}B pathway has been postulated to be important in signaling the cellular transcriptional response to CO2. In this study, we demonstrate that in cells exposed to elevated CO2, the NF-{kappa}B family member RelB was cleaved to a lower molecular weight form and translocated to the nucleus in both mouse embryonic fibroblasts and human pulmonary epithelial cells (A549). Furthermore, elevated nuclear RelB was observed in vivo and correlated with hypercapnia-induced protection against LPS-induced lung injury. Hypercapnia-induced RelB processing was sensitive to proteasomal inhibition by MG-132 but was independent of the activity of glycogen synthase kinase 3β or MALT-1, both of which have been previously shown to mediate RelB processing. Taken together, these data demonstrate that RelB is a CO2-sensitive NF-{kappa}B family member that may contribute to the beneficial effects of hypercapnia in inflammatory diseases of the lung.

Key Words: Acidosis • Carbon Dioxide • Chronic Obstructive Pulmonary Disease (COPD) • Inflammation • NF-{kappa}B • Acute Respiratory Distress Syndrome • Hypercapnia • RelB

Received for publication January 31, 2012.


1 Both authors contributed equally to this work.

2 To whom correspondence should be addressed: School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. Tel.: 353-1-716-6732; Fax: 353-1-716-670; E-mail: cormac.taylor{at}

Crosstalk between the equilibrative nucleoside transporter ENT2 and alveolar Adora2b adenosine receptors dampens acute lung injury.
T. Eckle, K. Hughes, H. Ehrentraut, K. S. Brodsky, P. Rosenberger, D.-S. Choi, K. Ravid, T. Weng, Y. Xia, M. R. Blackburn, et al. (2013)
FASEB J 27, 3078-3089
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882