Mediators of interleukin-1 beta action on the Na⁺-K ⁺ATPase in Caco-2 cells

Interleukin1-β has been demonstrated previously to reduce the activity and expression of the Na⁺-K⁺ pump in the rat jejunum and colon. This work attempts to elucidate the signal transduction pathway underlying its effect using Caco-2 cells. IL-1β reduced, in these cells also, the activity and expression of ATPase, in a dose- and time-dependent manner. The down-regulatory effect of the cytokine on the ATPase was not evident, when p38 MAP kinase was inhibited, but appeared in presence of inhibitors of MEK and NFκB, although activation of NF-κB was demonstrated by western blot analysis. The effect of IL-1β on the pump disappeared in the presence of indomethacin, a COX inhibitor. Exogenous PGE2 reduced the expression of the pump within 15 minutes, and this effect was still apparent when p38MAPK was inhibited. Curcumin, a JNK/AP-1 inhibitor, partially abolished the effect of IL-1β on ATPase expression but did not interfere with the effect of PGE2. These results indicate that IL-1β reduces the expression of ATPase independently of NFκB but, through a major pathway involving p38 and COX-2/PGE2, and another pathway involving JNK/AP1.