Negative Regulation of Hepatic Inflammation by the Soluble Resistance-Related Calcium-Binding Protein via Signal Transducer and Activator of Transcription 3.

Xiaying Li,Jue Liu,Xiang Gao,Yanan Liu,Xiaoqi Li,Shijun J Zheng,Hong Cao,Yongqiang Wang

doi:10.3389/fimmu.2017.00709

Abstract

Host immune response is tightly controlled by negative regulators to avoid excessive immune reactions for homeostasis. Some pathogens may take advantage of host negative regulating system to evade host defense. Our previous report showed that foot-and-mouth disease virus (FMDV) VP1 inhibited TNF-α- and SeV-induced type I interferon response via interaction with cellular protein soluble resistance-related calcium-binding protein (sorcin). Conversely, TNF-α- or SeV-induced type I interferon response increased when sorcin knocked down, leading to inhibition of vesicular stomatitis virus replication. However, the exact role of sorcin in regulation of the immune response is still not clear. Here, we show that mice deficient of sorcin (sorcin−/−) display enhanced ConA-induced hepatitis. Importantly, splenocytes from sorcin−/− mice produced more IL-2, IL-4, IL-17, and IFN-γ than that of littermate controls (sorcin+/+) in response to anti-CD3/28 stimulation. Furthermore, our data indicate that sorcin interacts with signal transducer and activator of transcription 3 (STAT3) and enhances its phosphorylation and that STAT3 acts as an immediate downstream molecule of sorcin in the negative regulation of NF-κB signaling. Thus, sorcin, in association with STAT3, negatively regulates hepatic inflammation.

Highlights

Host immune response is tightly controlled by negative regulators to avoid excessive immune reactions for homeostasis
Sorcin was originally identified in drug-resistant cells [13, 14]
Our previous report shows that sorcin inhibits type I interferon response in cells, suggesting that sorcin serves as an inhibitor for cell response [3]

Summary

INTRODUCTION

Host immune response is tightly controlled by negative regulators to avoid excessive immune reactions for homeostasis. Regulate Hepatitis by Sorcin via STAT3 soluble resistance-related calcium-binding protein (sorcin) [3] This observation suggests that sorcin might act as an important component of host negative regulating system that dampens cell response to viral infections. Lines of evidence showed that negative regulating proteins played an essential role in homeostasis, such as suppressors of SOCS proteins as counterparts for STAT [4, 5], Mdm as negative regulator for p53 [6,7,8], and CTLA4 as a brake for TCR-mediated T cell activation [9,10,11] Loss of these negative regulators leads to reinless cell responses to stimuli, resulting in varied disorders in animals. Our data show that sorcin interacted with STAT3 and enhanced STAT3 phosphorylation upon IL-6 treatment, indicating that sorcin, via interaction with STAT3, is involved in negative regulation of hepatic inflammation

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT