Reduced expression of IL-12 p35 by SJL/J macrophages responding to Theiler's virus infection is associated with constitutive activation of IRF-3.
Macrophages responding to viral infections may contribute to autoimmune demyelinating diseases (ADD). Macrophages from ADD-susceptible SJL/J mice responding to Theiler's Virus (TMEV) infection, the TLR7 agonist loxoribine, or the TLR4 agonist-LPS expressed less IL-12 p35 but more IL-12/23 p40 and IFN-beta than macrophages from ADD-resistant B10.S mice. While expression of IRF-1 and -7 was similar between B10.S and SJL/J TMEV-infected macrophages, SJL/J but not B10.S macrophages exhibited constitutively active IRF-3. In contrast to overexpressed IRF-1, IRF-5, and IRF-7, which stimulated p35 promoter reporter activity, overexpressed IRF-3 repressed p35 promoter activity in response to TMEV infection, loxoribine, IFN-gamma/LPS, but not IFN-gamma alone. IRF-3 lessened but did not eliminate IRF-1-stimulated p35 promoter activity. Repression by IRF-3 required bp -172 to -122 of the p35 promoter. The data suggest that pre-activated IRF-3 is a major factor in the differences in IL-12 production between B10.S and SJL/J macrophages responding to TMEV.
Dahlberg
Angela
A
Department of Oral Biology and Nebraska Center for Virology, University of Nebraska Medical Center, 40th and Holdrege Sts., Lincoln, NE 68583-0740, USA.
Auble
Mark R
MR
Petro
Thomas M
TM
D000818:Animals; D018188:Cardiovirus Infections / Q000276:immunology*; D002460:Cell Line; D020278:Demyelinating Autoimmune Diseases, CNS / Q000209:etiology; D015536:Down-Regulation; D005260:Female; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D053765:Interleukin-12 Subunit p35; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D021122:Protein Subunits / Q000378:metabolism*; D017945:Theilovirus; D013997:Time Factors
D050838:Interferon Regulatory Factor-3; D053765:Interleukin-12 Subunit p35; D021122:Protein Subunits; D018664:Interleukin-12