Excessive CO2 in the blood (hypercapnia) alters physiology both as an active signaling molecule and through acidosis. Although hypercapnia can have adverse effects, it can suppress nuclear factor κB (NF-κB)–dependent transcription of proinflammatory genes, and it is often induced to protect patients with pulmonary disease from inflammation-induced lung injury. Oliver et al. report that exposing mouse embryo fibroblasts (MEFs) or human pulmonary epithelial (A549) cells to 10% CO2 induced cleavage and nuclear translocation of the NF-κB family member RelB compared with cells cultured in ambient conditions (0.03% CO2). Lowering the pH of the culture medium under ambient conditions had no effect on the subcellular localization of RelB in MEFs. High CO2 also induced nuclear accumulation of the α subunit of inhibitor of NF-κB kinase (IKKα), which promotes RelB activation, but had no effect on the molecular mass or subcellular localization of the NF-κB family member p65. Treating MEFs with a proteasome inhibitor prevented the accumulation of cleaved RelB in the nucleus in cells cultured in 10% CO2 but had no effect on the nuclear accumulation of IKKα. Under ambient conditions, stimulation of A549 cells with the proinflammatory cytokine tumor necrosis factor–α (TNF-α) induced TNFα expression. High CO2 (10%) suppressed this induction, and knocking down RelB by RNA interference increased this suppressive effect. For rats treated with bacterial lipopolysaccharide (LPS) to induce acute lung injury, therapeutic hypoventilation with a gas mixture containing 5% CO2 induces hypercapnia, decreases inflammatory lung damage, and improves survival and lung function. Therapeutic hypoventilation also induced nuclear accumulation of RelB in lung leukocytes compared to animals ventilated without CO2 after LPS treatment. These results suggest a model in which CO2 induces proteasomal-dependent cleavage of RelB, which then translocates to the nucleus, where it reduces the expression of proinflammatory genes. Although nuclear translocation of NF-κB transcription factors is generally proinflammatory, NF-κB transcription factors form various active and inactive homo- and heterodimers, so the relative abundance of these proteins in the nucleus may determine whether or not NF-κB–responsive proinflammatory genes are activated.
K. M. Oliver, C. R. Lenihan, U. Bruning, A. Cheong, J. G. Laffey, P. McLoughlin, C. T. Taylor, E. P. Cummins, Hypercapnia induces cleavage and nuclear localization of RelB protein, giving insight into CO2 sensing and signaling. J. Biol. Chem. 287, 14004–14011 (2012). [Abstract] [Full Text]