title: IL-10-dependent S100A8 gene induction in monocytes/macrophages by double-stranded RNA.
abstract: The S100 calcium-binding proteins S100A8 and S100A9 are elevated systemically in patients with viral infections. The S100A8-S100A9 complex facilitated viral replication in human CD4(+) T lymphocytes latently infected with HIV-1- and S100A8-induced HIV-1 transcriptional activity. Mechanisms inducing the S100 genes and the potential source of these proteins following viral activation are unknown. In this study, we show that S100A8 was induced in murine macrophages, and S100A8 and S100A9 in human monocytes and macrophages, by polyinosinic:polycytidylic acid, a dsRNA mimetic. Induction was at the transcriptional level and was IL-10 dependent. Similar to LPS-induced S100A8, induction by dsRNA was dependent on p38 and ERK MAPK. Protein kinase R (PKR) mediates antiviral defense and participates in MyD88-dependent/independent signaling triggered by TLR4 or TLR3. Like IL-10, S100 induction by polyinosinic:polycytidylic acid and by LPS was inhibited by the specific PKR inhibitor 2-aminopurine, indicating a novel IL-10, PKR-dependent pathway. Other mediators such as IFN-beta, which synergized with dsRNA, may also be involved. C/EBPbeta bound the defined promoter region in response to dsRNA. S100A8 was expressed in lungs of mice infected with influenza virus and was maximal at day 8 with strong immunoreactivity in epithelial cells lining the airways and in mononuclear cells and declined early in the recovery phase, implying down-regulation by mediator(s) up-regulated during resolution of the infection. IL-10 is implicated in viral persistence. Since S100A8/S100A9 levels are likely to be maintained in conditions where IL-10 is raised, these proteins may contribute to viral persistence in patients infected by some RNA viruses.
authors.affiliation: Centre for Infection and Inflammation Research, School of Medical Sciences, University New South Wales, Sydney, Australia.
authors.forename: Yasumi
authors.initials: Y
authors.lastname: Endoh
authors.forename: Yuen Ming
authors.initials: YM
authors.lastname: Chung
authors.forename: Ian A
authors.initials: IA
authors.lastname: Clark
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Geczy
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hsu
mesh_terms: D000818:Animals; D040501:Calgranulin A / Q000235:genetics* / Q000378:metabolism; D040502:Calgranulin B / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D051379:Mice; D009000:Monocytes / Q000276:immunology* / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis; D011070:Poly I-C / Q000276:immunology; D012327:RNA Virus Infections / Q000276:immunology; D012330:RNA, Double-Stranded / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D019892:eIF-2 Kinase / Q000276:immunology / Q000378:metabolism
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D012330:RNA, Double-Stranded; D019892:eIF-2 Kinase; D011070:Poly I-C