Beta-arrestin 2 negatively regulates sepsis-induced inflammation.
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.
Fan
Hongkuan
H
Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA. fanhong@musc.edu
Bitto
Alessandra
A
Zingarelli
Basilia
B
Luttrell
Louis M
LM
Borg
Keith
K
Halushka
Perry V
PV
Cook
James A
JA
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D001769:Blood / Q000382:microbiology; D002432:Cecum / Q000201:enzymology; D007249:Inflammation / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010529:Peritoneal Cavity / Q000382:microbiology; D009195:Peroxidase / Q000378:metabolism; D018805:Sepsis / Q000150:complications* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605258:Arrb2 protein, mouse; D019390:Arrestins; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D016753:Interleukin-10; D009195:Peroxidase
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