Control of early Theiler's murine encephalomyelitis virus replication in macrophages by interleukin-6 occurs in conjunction with STAT1 activation and nitric oxide production.

Abstract

During Theiler's murine encephalomyelitis virus (TMEV) infection of macrophages, it is thought that high interleukin-6 (IL-6) levels contribute to the 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 lipopolysaccharide (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 upregulation of several antiviral genes downstream of STAT1. However, neither inhibition of IL-6-induced nitric oxide nor knockdown of STAT1 diminished the early antiviral 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 antiviral nitric oxide production and antiviral STAT1 activation. These results indicate that immediate-early production of IL-6 could protect macrophages from TMEV infection.

• Authors: Tyler C Moore, Katherine L Bush, Liz Cody, Deborah M Brown, Thomas M Petro
• Journal: Journal of virology (J Virol) Vol. 86 Issue 19 Pg. 10841-51 (Oct 2012) ISSN: 1098-5514 [Electronic] United States
• PMID: 22837198 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• Lipopolysaccharides
• STAT1 Transcription Factor
• STAT3 Transcription Factor
• Nitric Oxide
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Cell Line
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Interleukin-6 (metabolism)
• Lipopolysaccharides (chemistry)
• MAP Kinase Signaling System
• Macrophages (cytology)
• Mice
• Nitric Oxide (chemistry, metabolism)
• RNA Interference
• STAT1 Transcription Factor (metabolism)
• STAT3 Transcription Factor (metabolism)
• Theilovirus (immunology)
• Virus Replication