title: Effect of the N-butanoyl glutathione (GSH) derivative and acyclovir on HSV-1 replication and Th1 cytokine expression in human macrophages.
abstract: Macrophages are an important defense against in vivo herpes simplex virus (HSV) infection by early cytokine secretion; however, they can be infected by HSV-1 and they may be compromised in their ability to produce cytokines. In this paper, we studied the expression of two Th1 cytokines, interleukin (IL)-12 and IL-27, upon HSV-1 infection of human macrophages, and how it is regulated by treatment with two antiviral drugs exerting their anti-HSV-1 activity through different mechanisms of action. We found that infection does not alter intra-macrophage thiol content, while it induces mRNA expression of IL-12 p35 and IL-12 p40 as well as of IL-27 p28 and IL-27 EBI3, as revealed by RT-PCR. The increased expression of mRNA is accompanied by increased production of IL-12 p40 and IL-27 p28 protein, as detected in the culture supernatants by ELISA. The two antiviral drugs tested were acyclovir (ACV), commonly used to treat herpes virus infections, and an N-butanoyl glutathione (GSH) derivative, GSH-C4. While ACV inhibits viral DNA polymerase, GSH-C4 inhibits virus replication by interfering with protein folding and maturation of viral particles. Indeed, GSH-C4, altering the intracellular redox state, may modulate the Th1/Th2 balance favoring Th1-type response. Our data show that both drugs inhibit HSV-1 replication in macrophages, without significantly affecting cytokine mRNA levels. Nonetheless, lower levels of IL-12 p40 and IL-27 p28 proteins were found in the supernatants of macrophages treated with either GSH-C4 or ACV, likely as an indirect consequence of inhibited HSV-1 replication.
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Via Saffi, 2, 61029, Urbino, PU, Italy, alessandra.fraternale@uniurb.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fraternale
authors.forename: Giuditta Fiorella
authors.initials: GF
authors.lastname: Schiavano
authors.forename: Maria Filomena
authors.initials: MF
authors.lastname: Paoletti
authors.forename: Linda
authors.initials: L
authors.lastname: Palma
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
authors.forename: Giorgio
authors.initials: G
authors.lastname: Brandi
mesh_terms: D000212:Acyclovir / Q000494:pharmacology*; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007378:Interleukins; C464565:MYDGF protein, human; C562006:glutathione-C4; D018664:Interleukin-12; D005978:Glutathione; D000212:Acyclovir