NF-κB Links CO2 Sens ing to Innate Immuni ty and Inflammation in Mammalian Cells

Viktig studie som nevner at økt CO2 kan dempe betennelser.

In this study, we demonstrate that mammalian cells (mouse embryonic fibroblasts and others) also sense changes in local CO2 levels, leading to altered gene expression via the NF-κB pathway. IKKα, a central regulatory component of NF-κB, rapidly and reversibly translocates to the nucleus in response to elevated CO2. This response is independent of hypoxia-inducible factor hydroxylases, extracellular and intracellular pH, and pathways that mediate acute CO2-sensing in nematodes and flies and leads to attenuation of bacterial LPS-induced gene expression. These results suggest the existence of a molecular CO2 sensor in mammalian cells that is linked to the regulation of genes involved in innate immunity and inflammation.

FIGURE 7.Hypercapnia promotes an anti-inflammatory profile of gene expression. A PCR array of genes known to be involved in the NF-κB signaling cascade was performed on A549 cells exposed to ambient or 10% CO2 ± LT (100 ng/ml) for 4 h. A selection of differentially expressed genes from the array were chosen for validation. CCL2 (A), ICAM1 (B), TNF-α (C), and IL-10 (D) message levels were determined by quantitative real-time PCR and expressed as a percentage of LT-induced gene expression at 0.03% CO2 (n = 3 ± SEM, one-way ANOVA, Tukey post-test).

Traditionally, CO2 has been considered a waste product of respiration, and its biologic activity is poorly understood in terms of gene expression. However, a recent study reported differential gene expression in elevated CO2 (9).

This study suggests the existence of an intracellular CO2 sensor that is associated with anti-inflammatory and immunosuppressive signaling, is independent of intracellular and extracellular pH, and could account for the above clinical observations. CO2 can profoundly influence the transcriptional activation of the NF-κB pathway but its transcriptional effects may extend to other as yet uncharacterized pathways. Understanding the molecular mechanisms of CO2-dependent intracellular signaling could lead to new therapies in which the suppression of immunity or inflammation is clinically desirable.

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