Abstract

Porcine circovirus type 2 (PCV2) is one of the major threats to pig farms worldwide. Although PCV2 has been identified to promote IL-10 production, the detailed regulatory roles of PCV2 Rep for IL-10 production remain unclear. Herein, we first found that PCV2 Rep, rather than PCV1 Rep, enhanced IL-10 expression at the later phase of PCV2 infection in porcine alveolar macrophages (PAMs). Furthermore, we found that PCV2 Rep directly activated the p38-MAPK pathway to promote transcription factors NF-κB p50 and Sp1 binding to the il10 promoter, but PCV1 Rep did not. During PCV2 infection, however, PCV2 Rep promoted the binding activities of NF-κB p50 and Sp1 with the il10 promoter only at the later phase of PCV2 infection, since Rep proteins only expressed at the later phase of the infection. Moreover, silence of the thymine DNA glycosylase (TDG), a Rep-binding protein, significantly reduced the binding activities of NF-κB p50 and Sp1 with il10 promoter, resulting in the reduction of IL-10 production in PCV2-inoculated PAMs at the later phase of infection. Taken together, our results demonstrate that Rep proteins enhance IL-10 production during PCV2 infection of PAMs via activation of p38-MAPK pathways, in which host TDG is a critical mediator.

Highlights

  • Porcine circovirus type 2 (PCV2) aggressively spreads throughout the world and seriously hinders the economic development of the pig industry worldwide [1,2]

  • Previous studies have revealed that PCV2 infection induces IL-10 production in vivo and in vitro, whereas PCV1 does not show the same effect on IL-10 expression [21]

  • Akt specific siRNA, p38-mitogen-activated protein kinases (MAPKs) specific siRNA, and ERK specific siRNA could all downregulate IL-10 expression in PCV2-infected cells at 24 h p.i., as per our previous report (Figure 3C). These results suggest that PCV2 replication-associated protein (Rep) can upregulate IL-10 expression through enhancing the activity of the p38-MAPK signaling pathway

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Summary

Introduction

Porcine circovirus type 2 (PCV2) aggressively spreads throughout the world and seriously hinders the economic development of the pig industry worldwide [1,2]. PCV2 infection can increase the risk of porcine reproductive and respiratory syndrome virus (PRRSV), porcine parvovirus (PPV), and other viruses or bacteria infection, leading to porcine circovirus associated diseases (PCVAD) [3]. As one of the two largest genes in the PCV genome sequence, ORF1 encodes a 35.8 kDa virus replication-associated protein (Rep), which is considered to be necessary for viral replication and plays a vital role in cell-mediated immunity [5,6]. ORF1 is highly conserved between PCV1 and PCV2, they may play different roles in the virus-induced immune. As a key regulatory anti-inflammatory cytokine of multiple immune cells, IL-10 plays a pivotal role in limiting excessive inflammatory responses [10]. Our previous study has revealed that PCV2 infection promotes IL-10 expression, and mitogen-activated protein kinases (MAPKs) and phosphoinositide 3 kinase PI3K/Akt signaling pathways are involved in the regulation of IL-10 production in porcine alveolar macrophages (PAMs) during PCV2 infection [13]

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