Beta-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 NFkappaB. beta-Arrestins 1 and 2 have recently been implicated in modulation of NFkappaB 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 beta-arrestin 2 positively regulates LPS-induced ERK 1/2 activation and both beta-arrestins 1 and 2 negatively regulate LPS-induced NFkappaB activation. Also beta-arrestin 2 positively regulate LPS-induced IL-6 production and both beta-arrestins 1 and 2 positively regulate LPS-induced IL-8 production. The specific ERK1/2 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 ERK1/2 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 NFkappaB 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.
Fan
Hongkuan
H
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, United States.
Luttrell
Louis M
LM
Tempel
George E
GE
Senn
Joseph J
JJ
Halushka
Perry V
PV
Cook
James A
JA
D000818:Animals; D019390:Arrestins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D007378:Interleukins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3