Upregulation of RGS4 expression by IL-1β in colonic smooth muscle is enhanced by ERK1/2 and p38 MAPK and inhibited by the PI3K/Akt/GSK3β pathway

Hu W, Li F, Mahavadi S, Murthy KS. Upregulation of RGS4 expression by IL-1 beta in colonic smooth muscle is enhanced by ERK1/2 and p38 MAPK and inhibited by the PI3K/Akt/GSK3 beta pathway. Am J Physiol Cell Physiol 296: C1310-C1320, 2009; doi:10.1152/ajpcell.00573.2008.- Initial Ca2+-dependent contraction of intestinal smooth muscle is inhibited upon IL-1 beta treatment. The decrease in contraction reflects the upregulation of regulator of G protein signaling-4 (RGS4) via the canonical inhibitor of NF-kappa B kinase-2 (IKK2)/I kappa B-alpha/NF-kappa B pathway. Here, we show that the activation of various protein kinases, including ERK1/2, p38 MAPK, and phosphoinositide 3-kinase (PI3K), differentially modulates IL-1 beta-induced upregulation of RGS4 in rabbit colonic muscle cells. IL-1 beta treatment caused a transient phosphorylation of ERK1/2 and p38 MAPK. It also caused the phosphorylation of Akt and glycogen synthase kinase-3 beta (GSK3 beta), sequential downstream effectors of PI3K. Pretreatment with PD-98059 (an ERK inhibitor) and SB-203580 (a p38 MAPK inhibitor) significantly inhibited IL-1 beta-induced RGS4 expression. In contrast, LY-294002 (a PI3K inhibitor) augmented, whereas GSK3 beta inhibitors inhibited, IL-1 beta-induced RGS4 expression. PD-98059 blocked IL-1 beta-induced phosphorylation of IKK2, degradation of I kappa B-alpha, and phosphorylation and nuclear translocation of NF-kappa B subunit p65, whereas SB-203580 had a marginal effect, implying that the effect of ERK1/2 is exerted on the canonical IKK2/I kappa B-alpha/p65 pathway of NF-kappa B activation but that the effect of p38 MAPK may not predominantly involve NF-kappa B signaling. The increase in RGS4 expression enhanced by LY-294002 was accompanied by an increase in the phosphorylation of IKK2/I kappa B-alpha/p65 and blocked by pretreatment with inhibitors of IKK2 (IKK2-IV) and I kappa B-alpha (MG-132). Inhibition of GSK3 beta abolished IL-1 beta-induced phosphorylation of IKK2/p65. These findings suggest that ERK1/2 and p38 MAPK enhance IL-1 beta-induced upregulation of RGS4; the effect of ERK1/2 reflects its ability to promote IKK2 phosphorylation and increase NF-kappa B activity. GSK3 beta acts normally to augment the activation of the canonical NF-kappa B signaling. The PI3K/Akt/GSK3 beta pathway attenuates IL-1 beta-induced upregulation of RGS4 expression by inhibiting NF-kappa B activation.