title: beta-Arrestins modulate Adenovirus-vector-induced innate immune responses: differential regulation by beta-arrestin-1 and beta-arrestin-2.
abstract: Adenovirus (Ad)-based vectors have been utilized in human gene transfer clinical trials since 1993. Unfortunately, innate immune responses directed against the Ad capsid and/or its genetic cargo can significantly limit the usage of Ad vectors. Previous studies have demonstrated that several signaling pathways are triggered by Ads, inclusive of TLR-dependent pathways. The G-protein-coupled receptor adaptors beta-arrestin-1 (beta-Arr1) and beta-arrestin-2 (beta-Arr2) are known to have pivotal roles in regulating TLR4 triggered signaling and inflammatory responses. In this study, we examined the role of beta-arrestins in Ad5-vector-induced inflammatory responses. Our studies reveal that both beta-arrestins are capable of modulating Ad5-vector-induced inflammatory responses in vivo and in vitro. Importantly, our studies divulge another level of complexity to these responses, as our results demonstrate beta-Arr1 to be a positive regulator, and beta-Arr2 a negative regulator of Ad5 induced innate immune responses. These data may allow gene therapy biologists to more accurately study the mechanisms underlying Ad5-vector-induced immune responses, and may also direct future efforts to modulate these mechanisms to improve the safety and/or efficacy of this important gene transfer vector.
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Seregin
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Appledorn
authors.forename: Sonika
authors.initials: S
authors.lastname: Patial
authors.forename: M
authors.initials: M
authors.lastname: Bujold
authors.forename: W
authors.initials: W
authors.lastname: Nance
authors.forename: S
authors.initials: S
authors.lastname: Godbehere
authors.forename: Narayanan
authors.initials: N
authors.lastname: Parameswaran
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D000260:Adenoviruses, Human / Q000276:immunology*; D000818:Animals; D019390:Arrestins / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D056747:Immunomodulation; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D016207:Cytokines; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins