Hypercapnia induces cleavage and nuclear localization of REL B giving insight into co2 sensing and signalling
Oliver, Kathryn M Lenihan, Colin R BRUENING ROSSOW, Ulrike Cheong, Alex Laffey, John G McLoughlin, Paul Taylor, Cormac T × Cummins, Eoin P #
American Society for Biochemistry and Molecular Biology
Journal of Biological Chemistry
Carbon dioxide (CO2) is increasingly being appreciated as an intracellular signalling molecule which affects inflammatory and immune responses. Elevated arterial CO2 (hypercapnia) is encountered in a range of clinical conditions including chronic obstructive pulmonary disease (COPD) and as a consequence of therapeutic ventilation in acute respiratory distress syndrome (ARDS). In patients suffering from ARDS, therapeutic hypoventilation strategy designed to reduce mechanical damage to the lungs is accompanied by systemic hypercapnia and associated acidosis which is 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-κB pathway has been postulated as being important in signalling the cellular transcriptional response to CO2. In the current study, we demonstrate that in cells exposed to elevated CO2, the NF-κB family member RelB is cleaved to a lower molecular weight form and translocates to the nucleus both in mouse embryonic fibroblasts and in human pulmonary epithelial cells (A549). Furthermore, elevated nuclear RelB was observed in vivo and correlates with hypercapnia-induced protection against LPS-induced lung injury. Hypercapnia-induced RelB processing is sensitive to proteosomal inhibition by MG-132 but is independent of the activity of GSK3β or MALT-1 which have been previously shown to mediate RelB processing. Taken together, these data demonstrate that RelB is a CO2-senistive NF-κB family member which may contribute to the beneficial effects of hypercapnia in inflammatory diseases of the lung.