title: 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: School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA.
authors: Tyler C
authors: TC
authors: Moore
authors: Katherine L
authors: KL
authors: Bush
authors: Liz
authors: L
authors: Cody
authors: Deborah M
authors: DM
authors: Brown
authors: Thomas M
authors: TM
authors: Petro
mesh_terms: D000818:Animals; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000166:cytology; D051379:Mice; D009569:Nitric Oxide / Q000737:chemistry* / Q000378:metabolism; D034622:RNA Interference; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017945:Theilovirus / Q000276:immunology*; D014779:Virus Replication
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D009569:Nitric Oxide; D048049:Extracellular Signal-Regulated MAP Kinases