Ambivalent roles of early growth response 1 in inflammatory signaling following ribosomal insult in human enterocytes

Abstract

NF-κB expression and activity are strictly regulated in gut epithelia to prevent overstimulation of pro-inflammatory responses following exposure to commensal bacteria. The effects of epithelial EGR-1 on responses to bacterial NF-κB-activating lipopolysaccharide (LPS) in intestinal epithelial cells under ribosomal stress were assessed. This was done to determine the potential of EGR-1 as a modulator of epithelial NF-κB signaling. Nuclear translocation of phosphorylated p65 protein was observed in the cells exposed to LPS although chemokine expression was marginally affected. In contrast, simultaneous exposure to LPS and ribosomal insults prevented epithelial NF-κB activation while chemokine expression was enhanced. The effect of EGR-1, another pro-inflammatory signaling mediator, was monitored to determine the involvement of this factor on chemokine production in response to this co-treatment. Similar to the previously reported ribosomal stress response, EGR-1 expression was elevated by ribosomal insults alone and positively affected gene expression of pro-inflammatory chemokines in the intestinal epithelial cells. However, EGR-1 suppression led to super-induction of chemokines by simultaneous treatment with LPS and ribosomal insult, indicating that EGR-1 is a negative modulator of chemokine gene expression. Particularly, mucosal ribosomal insult-triggered EGR-1 mediated PPARγ induction, which counteracted NF-κB activation by LPS. It can be thus concluded that EGR-1 regulates pro-inflammatory NF-κB activation by LPS via PPARγ although EGR-1 is a positive mediator of chemokine expression following ribosomal insult in intestinal epithelial cells.