Interleukin-1 receptor antagonist: an early immunomodulatory cytokine induced by porcine reproductive and respiratory syndrome virus

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) infection poorly induces pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) and type I IFN production during the early phase of infection. Our microarray analysis indicated strong upregulation of the IL1RA gene in type 2 PRRSV -infected monocyte-derived dendritic cells. Interleukin-1 receptor antagonist (IL-1Ra) is an early inhibitory cytokine that suppresses pro-inflammatory cytokines and T-lymphocyte responses. To investigate the induction of IL-1Ra by PRRSV, monocyte-derived dendritic cells were cultured with type 2 PRRSV or other swine viruses. PRRSV increased both IL1RA gene expression and IL-1Ra protein production in the culture. The enhanced production of IL-1Ra was further confirmed in PRRSV-cultured PBMC and PRRSV-exposed pigs by flow cytometry. Myeloid cell population appeared to be the major IL-1Ra producer both in vitro and in vivo. In contrast to the type 2 PRRSV, the highly pathogenic (HP)- PRRSV did not upregulate IL1RA gene expression in vitro. To determine the kinetics of PRRSV-induced IL1RA gene expression in relation to other pro-inflammatory cytokine genes, PRRSV-negative pigs were vaccinated with a commercially available type 2 modified-live PRRS vaccine or intranasally inoculated with HP-PRRSV. In modified-live PRRS vaccine pigs, upregulation of IL1RA, but not IL1B and IFNA, gene expression was observed from 2 days post- vaccination. Consistent with the in vitro findings, upregulation of IL1RA gene expression was not observed in the HP-PRRSV-infected pigs throughout the experiment. This study identified IL-1Ra as an early immunomodulatory mediator that could be involved in the immunopathogenesis of PRRSV infections.

Negative Immunomodulatory Effects of Type 2 Porcine Reproductive and Respiratory Syndrome Virus-Induced Interleukin-1 Receptor Antagonist on Porcine Innate and Adaptive Immune Functions

“…Interleukin-1 receptor antagonist (IL-1Ra) is known as an early inhibitory cytokine, which potentially participates in PRRSV-induced immunosuppression during the early phase of infection (26). As several reports showed that IL-1Ra is a potent negative immunomodulator of both innate and adaptive immune functions (51–53), the present study extended the characterization of the negative immunomodulatory effects of PRRSV-induced IL-1Ra on several aspects of porcine immune functions.…”

“…Although our observations on the negative immunomodulatory effects of PRRSV-induced IL-1Ra were obtained using in vitro assays, these circumstances are likely relevant to PRRSV-induced immunosuppression in the infected pigs in regard to impaired innate cytokine production (16, 92), prolonged PRRSV-specific T helper and CTL induction (93), and enhanced PRRSV-specific Treg population (22, 24, 94). In contrast, highly pathogenic (HP)-PRRSV infection, which is deficient in its ability for IL-1Ra induction (26), causes robust innate cytokine production in an early phase of infection (95). These findings support our notion that IL-1Ra is, in part, responsible for negative immune responses in the PRRSV-infected pigs.…”

“…Levels of porcine IFNA, IL1, IL6, TBET, GATA3, RORGT, FOXP3 , and GAPDH expression were quantified by SYBR green-based qPCR using the specific primer sets shown in Table 1. qPCR reaction was carried out as previously described (26, 35–37). Ct values of each gene were normalized against the housekeeping gene; GAPDH .…”

“…Recently, interleukin-1 receptor antagonist (IL-1Ra) induced by PRRSV was suggested to play an important role during the early phase of PRRSV infection as increased levels of IL-1Ra were observed both in vitro and in PRRSV-infected pigs (26). Although effect of IL-1Ra on porcine immune responses remains elusive, several evidences have been shown in both human and mouse models.…”

Porcine FcεRI Mediates Porcine Reproductive and Respiratory Syndrome Virus Multiplication and Regulates the Inflammatory Reaction

“…Proinflammatory cytokines (TNF-a, IL-1 and IL-6) are induced after infection by PRRSV (Nedumpun et al 2017). PRRSV tends to attack the lungs and lymphoid organs and can proliferate in a variety of cells, such as porcine alveolar macrophages (PAMs), bone marrow-derived dendritic cells (BMDCs) and MARC-145 cells (Duan et al 1997;Gao et al 2016;Zhang et al 2016).…”