title: beta-Arrestin 2: a Negative Regulator of Inflammatory Responses in Polymorphonuclear Leukocytes.
abstract: 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.forename: Fahmin
authors.initials: F
authors.lastname: Basher
authors.forename: Hongkuan
authors.initials: H
authors.lastname: Fan
authors.forename: Basilia
authors.initials: B
authors.lastname: Zingarelli
authors.forename: Keith T
authors.initials: KT
authors.lastname: Borg
authors.forename: Lou M
authors.initials: LM
authors.lastname: Luttrell
authors.forename: George E
authors.initials: GE
authors.lastname: Tempel
authors.forename: Perry V
authors.initials: PV
authors.lastname: Halushka
authors.forename: James A
authors.initials: JA
authors.lastname: Cook