부산대학교 도서관

β-arrestins 1 and 2 are ubiquitously expressed proteins that alter signalling by G-protein-coupled receptors. β-arrestin 2 plays an important role as a signalling adaptor and scaffold in regulating cellular inflammatory responses. We hypothesized that β-arrestin 2 is a critical modulator of inflammatory response in experimental sepsis. β-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 β-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 β-arrestin 2(−/−) compared with WT mice. β-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 β-arrestin 2(−/−) and WT mice and stimulated in vitro with lipopolysaccharide (LPS). Tumour necrosis factor (TNF)-α, 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 β-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-α and IL-6 production upon LPS stimulation between WT and β-arrestin 2(−/−) mice. Our data demonstrate that β-arrestin 2 functions to negatively regulate the inflammatory response in polymicrobial sepsis. [ABSTRACT FROM AUTHOR]