Interleukin-6 control of early Theiler’s Murine Encephalomyelitis Virus replication in macrophages occurs in conjunction with STAT1 activation and nitric oxide production.

Authors

• Tyler C. Moore, University of Nebraska-LincolnFollow
• Katherine L. Bush, University of Nebraska Medical Center
• Deborah M. Brown, University of Nebraska-LincolnFollow
• Thomas M. Petro, University of Nebraska Medical CenterFollow

Document Type

Article

Date of this Version

2012

Citation

JVI Accepts, published online ahead of print on 25 July 2012

Journal of Virology, doi:10.1128/JVI.01402-12

Comments

Copyright © 2012, American Society for Microbiology. Used by permission.

Abstract

During Theiler’s virus (TMEV) infection of macrophages it is thought that high IL-6 levels contribute to demyelinating disease found in chronically infected SJL/J mice but absent in B10.S mice capable of clearing the infection. Therefore, IL-6 expression was measured in TMEV-susceptible SJL/J and TMEV-resistant B10.S macrophages during their infection with TMEV DA strain or responses to LPS or poly I:C. Unexpectedly, IL-6 production was greater in B10.S macrophages than SJL/J macrophages during the first 24 h after stimulation with TMEV, LPS or poly I:C. Further experiments showed that in B10.S, SJL/J, and RAW264.7 macrophage cells, IL-6 expression was dependent on extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) and enhanced by exogenous IL-12. In SJL/J and RAW264.7 macrophages, exogenous IL-6 resulted in decreased TMEV replication, earlier activation of STAT1 and STAT3, production of nitric oxide, and earlier up-regulation of several anti-viral genes downstream of STAT1. However, neither inhibition of IL-6-induced nitric oxide nor knockdown of STAT1 diminished the early anti-viral effect of exogenous IL-6. In addition, neutralization of endogenous IL-6 from SJL/J macrophages with Fab antibodies did not exacerbate early TMEV infection. Therefore, endogenous IL-6 expression after TMEV infection is dependent on ERK MAPK, enhanced by IL-12, but too slow to decrease viral replication during early infection. In contrast, exogenous IL-6 enhances macrophage control of TMEV infection through preemptive anti-viral nitric oxide production and anti-viral STAT1 activation. These results indicate that immediate early production of IL-6 could protect macrophages from TMEV infection.