HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/C1310    most recent 00573.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Hu, W. Articles by Murthy, K. S. PubMed PubMed Citation Articles by Hu, W. Articles by Murthy, K. S.

MUSCLE CELL BIOLOGY AND CELL MOTILITY

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

¹Department of Physiology and Biophysics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia; and ²Department of Neuroscience, Temple University School of Medicine, Philadelphia, Pennsylvania

Submitted 7 November 2008 ; accepted in final form 9 April 2009

Initial Ca²⁺-dependent contraction of intestinal smooth muscle is inhibited upon IL-1β treatment. The decrease in contraction reflects the upregulation of regulator of G protein signaling-4 (RGS4) via the canonical inhibitor of NF-B kinase-2 (IKK2)/IB-/NF-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-1β-induced upregulation of RGS4 in rabbit colonic muscle cells. IL-1β treatment caused a transient phosphorylation of ERK1/2 and p38 MAPK. It also caused the phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β), sequential downstream effectors of PI3K. Pretreatment with PD-98059 (an ERK inhibitor) and SB-203580 (a p38 MAPK inhibitor) significantly inhibited IL-1β-induced RGS4 expression. In contrast, LY-294002 (a PI3K inhibitor) augmented, whereas GSK3β inhibitors inhibited, IL-1β-induced RGS4 expression. PD-98059 blocked IL-1β-induced phosphorylation of IKK2, degradation of IB-, and phosphorylation and nuclear translocation of NF-B subunit p65, whereas SB-203580 had a marginal effect, implying that the effect of ERK1/2 is exerted on the canonical IKK2/IB-/p65 pathway of NF-B activation but that the effect of p38 MAPK may not predominantly involve NF-B signaling. The increase in RGS4 expression enhanced by LY-294002 was accompanied by an increase in the phosphorylation of IKK2/IB-/p65 and blocked by pretreatment with inhibitors of IKK2 (IKK2-IV) and IB- (MG-132). Inhibition of GSK3β abolished IL-1β-induced phosphorylation of IKK2/p65. These findings suggest that ERK1/2 and p38 MAPK enhance IL-1β-induced upregulation of RGS4; the effect of ERK1/2 reflects its ability to promote IKK2 phosphorylation and increase NF-B activity. GSK3β acts normally to augment the activation of the canonical NF-B signaling. The PI3K/Akt/GSK3β pathway attenuates IL-1β-induced upregulation of RGS4 expression by inhibiting NF-B activation.

smooth muscle cells; rabbit; short interfering RNA; nuclear factor-B; signal transduction; regulator of G protein signaling; interleukin-1β; extracellular signal-regulated kinase 1/2; mitogen-activated protein kinase; phosphoinositide 3-kinase