Document Detail


beta-Arrestin 2: a Negative Regulator of Inflammatory Responses in Polymorphonuclear Leukocytes.
MedLine Citation:
PMID:  19079685     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
Heterotrimeric Gi proteins have been previously implicated in signaling leading to inflammatory mediator production induced by bacterial lipopolysaccharide (LPS). beta-arrestins are ubiquitously expressed proteins that alter G-protein-coupled receptors signaling. beta-arrestin 2 plays a multifaceted role as a scaffold protein in regulating cellular inflammatory responses. Polymorphonuclear leukocytes (PMNs) activated by LPS induce inflammatory responses resulting in organ injury during sepsis. We hypothesized that beta-arrestin 2 is a critical modulator of inflammatory responses in PMNs. To examine the potential role of beta-arrestin 2 in LPS-induced cellular activation, we studied homozygous beta-arrestin 2 (-/-), heterozygous (+/-), and wildtype (+/+) mice. PMNs were stimulated with LPS for 16h. There was increased basal TNFalpha and IL-6 production in the beta-arrestin 2 (-/-) compared to both beta-arrestin 2 (+/-) and (+/+) cells. LPS failed to stimulate TNFalpha production in the beta-arrestin 2 (-/-) PMNs. However, LPS stimulated IL-6 production was increased in the beta-arrestin 2 (-/-) cells compared to (+/+) cells. In subsequent studies, peritoneal PMN recruitment was increased 81% in the beta-arrestin 2 (-/-) mice compared to (+/+) mice (p<0.05). beta-arrestin 2 deficiency resulted in an augmented expression of CD18 and CD62L (p<0.05). In subsequent studies, beta-arrestin 2 (-/-) and (+/+) mice were subjected to cecal ligation and puncture (CLP) and lung was collected and analyzed for myeloperoxidase activity (MPO) as index of PMNs infiltrate. CLP-induced MPO activity was significantly increased (p<0.05) in the beta-arrestin 2 (-/-) compared to (+/+) mice. These studies demonstrate that beta-arrestin 2 is a negative regulator of PMN activation and pulmomary leukosequestration in response to polymicrobial sepsis.
Authors:
Fahmin Basher; Hongkuan Fan; Basilia Zingarelli; Keith T Borg; Lou M Luttrell; George E Tempel; Perry V Halushka; James A Cook
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Publication Detail:
Type:  Journal Article     Date:  2008-01-20
Journal Detail:
Title:  International journal of clinical and experimental medicine     Volume:  1     ISSN:  1940-5901     ISO Abbreviation:  Int J Clin Exp Med     Publication Date:  2008  
Date Detail:
Created Date:  2008-12-16     Completed Date:  2011-07-14     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  101471010     Medline TA:  Int J Clin Exp Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  32-41     Citation Subset:  -    
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Grant Support
ID/Acronym/Agency:
R01 GM067202/GM/NIGMS NIH HHS
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