β-Arrestins 1 and 2 differentially regulate LPS-induced signaling and pro-inflammatory gene expression

Toll like receptors, the critical receptor family in innate immunity, have been shown to signal via both ERK 1/2 and transcription factor NF kappa B. beta-Arrestins 1 and 2 have recently been implicated in modulation of NF kappa B signaling and ERK 1/2 activation. Using a number of approaches: mouse embryonic fibroblasts (MEF) from wild-type (WT), beta-arrestins knockouts (KO), beta-arrestins 1 and 2 double KO, and MEFs with reconstituted WT beta-arrestins in the double KO cells, RNA interference (siRNA) specific knockdown of beta-arrestins, and overexpression of WT beta-arrestins, it was demonstrated that P-arrestin 2 positively regulates LPS-induced ERK 1/2 activation and both beta-arrestins 1 and 2 negatively regulate LPS-induced NF kappa B activation. Also P-arrestin 2 positively regulate LPS-induced IL-6 production and both beta-arrestins I and 2 positively regulate LPS-induced IL-8 production. The specific ERK 1/2 inhibitor PD98059 significantly decreased LPS-induced IL-6 and IL-8 production suggesting that IL-6 and IL-8 production is, in part, mediated by ERK 1/2 activation. Over expression of wild type beta-arrestins 1 and 2 had no effect on LPS-induced ERK 1/2 activation and LPS-induced IL-8 production suggesting that endogenous beta-arrestins 1 and 2 are sufficient to mediate maximum ERK 1/2 activity and IL-8 production. beta-Arrestins thus not only negatively regulate LPS-induced NF kappa B activation but also positively regulate ERK 1/2 activation and specific pro-inflammatory gene expression. Understanding the role of beta-arrestins in regulation of TLR signaling pathways may provide novel insights into control mechanisms for inflammatory gene expression. (c) 2007 Elsevier Ltd. All rights reserved.