Lipopolysaccharide (LPS) is a potent microbial
virulence factor that can trigger production of proinflammatory mediators involved in the pathogenesis of localized and systemic
inflammation. Importantly, the role of nuclear transport of stress responsive
transcription factors in this LPS-generated "genomic storm" remains largely undefined. We developed a new nuclear transport modifier (NTM)
peptide, cell-penetrating cSN50.1, which targets nuclear transport shuttles
importin α5 and
importin β1, to analyze its effect in LPS-induced localized (
acute lung injury) and systemic (lethal endotoxic
shock) murine
inflammation models. We analyzed a human genome database to match 46 genes that encode
cytokines,
chemokines and their receptors with
transcription factors whose nuclear transport is known to be modulated by NTM. We then tested the effect of
cSN50.1 peptide on proinflammatory gene expression in murine bone marrow-derived macrophages stimulated with LPS. This NTM suppressed a proinflammatory transcriptome of 37 out of 84 genes analyzed, without altering expression of housekeeping genes or being cytotoxic. Consistent with gene expression analysis in primary macrophages, plasma levels of 23 out of 26 LPS-induced proinflammatory
cytokines,
chemokines, and
growth factors were significantly attenuated in a murine model of LPS-induced systemic
inflammation (lethal endotoxic
shock) while the anti-inflammatory
cytokine,
interleukin 10, was enhanced. This anti-inflammatory reprogramming of the
endotoxin-induced genomic response was accompanied by complete protection against lethal endotoxic
shock with prophylactic NTM treatment, and 75% protection when NTM was first administered after LPS exposure. In a murine model of localized
lung inflammation caused by direct airway exposure to LPS, expression of
cytokines and
chemokines in the bronchoalveolar space was suppressed with a concomitant reduction of neutrophil trafficking. Thus, calming the LPS-triggered "genomic storm" by modulating nuclear transport with
cSN50.1 peptide attenuates the systemic inflammatory response associated with lethal
shock as well as localized
lung inflammation.