title: CD46-utilizing adenoviruses inhibit C/EBPbeta-dependent expression of proinflammatory cytokines.
abstract: The majority of adenovirus serotypes utilize the coxsackievirus-adenovirus receptor (CAR) for virus-host cell attachment, but subgroup B and subgroup D (adenovirus type 37 [Ad37]) viruses recognize CD46. CD46 is a ubiquitously expressed receptor that serves as a cofactor for the inactivation of the complement components C3b and C4b, and it also serves as a receptor for diverse microbial pathogens. A reported consequence of CD46 engagement is a reduced capability of human immune cells to express interleukin-12 (IL-12), a cytokine involved in both the innate and adaptive immune responses. Studies were thus undertaken to determine whether CD46-utilizing Ads alter the expression of proinflammatory cytokines. Subgroup B (Ad16 and -35) and Ad37, but not Ad2 or -5, significantly reduced IL-12 production by human peripheral blood mononuclear cells stimulated with gamma interferon (IFN-gamma) and lipopolysaccharide. IL-12 mRNA (p35 and p40 subunits) levels as well as other cytokine mRNA levels (IL-1alpha and -beta, IL-1Ra, and IL-6) were decreased upon interaction with CD46-utilizing Ads. Analysis of transcription factor activity required for cytokine expression indicated that CD46-utilizing Ads preferentially inhibited IFN-gamma-induced C/EBPbeta protein expression, consequently reducing its ability to form DNA complexes. Interference with IFN-gamma signaling events by CD46-utilizing Ads, but not CAR-utilizing Ads, reveals a potentially critical difference in the host immune response against distinct Ad vectors, a situation that has implications for gene delivery and vaccine development.
authors.affiliation: The Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Milena
authors.initials: M
authors.lastname: Iacobelli-Martinez
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Nepomuceno
authors.forename: Jodi
authors.initials: J
authors.lastname: Connolly
authors.forename: Glen R
authors.initials: GR
authors.lastname: Nemerow
mesh_terms: D000256:Adenoviridae / Q000276:immunology* / Q000502:physiology; D000257:Adenoviridae Infections / Q000276:immunology*; D015703:Antigens, CD / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011991:Receptors, Virus / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D015703:Antigens, CD; D022762:CCAAT-Enhancer-Binding Proteins; C497857:CD46 protein, human; D016207:Cytokines; C497249:DDIT3 protein, human; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011991:Receptors, Virus; D012795:Sialoglycoproteins; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D018664:Interleukin-12; D007371:Interferon-gamma