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-β, which synergized with dsRNA, may also be involved. C/EBPβ 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.

S-Glutathionylation Regulates Inflammatory Activities of S100A9

“…Hence, changes in intracellular/extracellular redox are likely to regulate their functional properties. Moreover, their dependence on IL-10 for induction in activated human monocytes/macrophages by TLR-3 and -4 ligands (26) and their enhanced expression in various cells by anti-inflammatory agents such as corticosteroids (25) implicates A8 and A9 in resolution of inflammation.…”

“…S-Thiolated actin was generated in PMA-activated neutrophils (21) and may be important in cell spreading and cytoskeletal organization (22). S100A8 (A8, MRP 8, calgranulin A) and S100A9 (A9, MRP 14, calgranulin B) are highly expressed in neutrophils (comprise ϳ40% of cytoplasmic proteins (23)) and induced in numerous cells, including monocytes (24), macrophages (25)(26)(27), and keratinocytes (28,29) by inflammatory mediators or oxidative stress. A8 and A9 heterocomplexes (A8/A9) are secreted after neutrophil activation (30) or released as a result of necrosis (31) and have chemotactic (32), anti-microbial (33,34), pro-apoptotic, and anti-proliferative (35,36) activities.…”

S100A8 Induces IL-10 and Protects against Acute Lung Injury

“…It is induced in several cell types by inflammatory mediators or by oxidative stress (6). In murine macrophages, S100A8 is induced by TLR agonists in the absence of S100A9 (7,8), and although some functions depend on heterocomplex formation, they can function independently (reviewed in Ref. 9).…”

Damage-Associated Molecular Pattern S100A9 Increases Bactericidal Activity of Human Neutrophils by Enhancing Phagocytosis

“…These proteins are highly expressed in neutrophils, representing close to 40% of total cytoplasmic proteins (7). Their expression is also inductible by multiple factors in monocytes (8), macrophages (9), and endothelial cells (10). These proteins are liberated as homo-or heterodimers after phagocyte activation (11), cell necrosis, or by the formation of neutrophil extracellular traps (12), where they act as danger signals for the organism presumably by activating TLR4 (13) or the receptor for advanced glycation end products (14).…”