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Immunology. 2010 Jul;130(3):344-51. doi: 10.1111/j.1365-2567.2009.03185.x. Epub 2010 May 4.

Beta-arrestin 2 negatively regulates sepsis-induced inflammation.

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  • 1Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA. fanhong@musc.edu

Abstract

SUMMARY:

Beta-arrestins 1 and 2 are ubiquitously expressed proteins that alter signalling by G-protein-coupled receptors. beta-arrestin 2 plays an important role as a signalling adaptor and scaffold in regulating cellular inflammatory responses. We hypothesized that beta-arrestin 2 is a critical modulator of inflammatory response in experimental sepsis. beta-arrestin 2(-/-) and wild-type (WT) mice were subjected to caecal ligation and puncture (CLP). The survival rate was significantly decreased (P < 0.05) in beta-arrestin 2(-/-) mice (13% survival) compared with WT mice (53% survival). A second group of mice were killed 18 hr after CLP for blood, peritoneal lavage and tissue sample collection. CLP-induced plasma interleukin (IL)-6 was significantly increased 25 +/- 12 fold and caecal myeloperoxidase (MPO) activity was increased 2.4 +/- 0.3 fold in beta-arrestin 2(-/-) compared with WT mice. beta-arrestin 2(-/-) mice exhibited more severe lung damage and higher bacterial loads compared with WT mice post CLP challenge as measured by histopathology and colony-forming unit count. In subsequent experiments, splenocytes, peritoneal macrophages and bone marrow-derived macrophages (BMDMs) were isolated and cultured from beta-arrestin 2(-/-) and WT mice and stimulated in vitro with lipopolysaccharide (LPS). Tumour necrosis factor (TNF)-alpha, IL-6 and IL-10 production induced by LPS was significantly augmented (2.2 +/- 0.2 fold, 1.8 +/- 0.1 fold, and 2.2 +/- 0.4 fold, respectively; P < 0.05) in splenocytes from beta-arrestin 2(-/-) mice compared with WT mice. The splenocyte response was different from that of peritoneal macrophages or BMDMs, which exhibited no difference in TNF-alpha and IL-6 production upon LPS stimulation between WT and beta-arrestin 2(-/-) mice. Our data demonstrate that beta-arrestin 2 functions to negatively regulate the inflammatory response in polymicrobial sepsis.

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