title: Disparate expression of IL-12 by SJL/J and B10.S macrophages during Theiler's virus infection is associated with activity of TLR7 and mitogen-activated protein kinases.
abstract: Differences in components of innate anti-viral immune responses may account for the contrast in susceptibility to Theiler's murine encephalomyelitis virus (TMEV) between SJL/J and B10.S mice. Herein, the expression of IL-12, interferon (IFN)-beta, Toll-like receptors 3 (TLR3), TLR7, and mitogen-activated protein (MAP)-kinases was evaluated in SJL/J and B10.S macrophages infected with TMEV. Twenty-four hours after infection, SJL/J macrophages exhibited higher levels of TMEV RNA, IL-12 p40, and TLR3 but lower levels of IL-12 p70 and the IL-12 p35 subunit compared with B10.S macrophages. Addition of exogenous IL-12 p70 or IFN-beta increased the resistance of SJL/J macrophages to TMEV infection. To assess MAP-kinases, macrophages were pretreated with the p38 MAP-kinase inhibitor SB203580 or extracellular signal-regulated kinases (ERK) MAP-kinase inhibitor U0126 before TMEV infection. U0126 reduced SJL/J but increased B10.S macrophage expression of IL-12 p40 and p70 in response to TMEV. U0126 decreased the IL-12 p35 response of SJL/J macrophages. To assess TLR7, SJL/J and B10.S macrophages were stimulated with loxoribine, a TLR7 ligand. Loxoribine induced more IL-12 p70 production and p35 expression in B10.S than SJL/J macrophages. U0126 increased loxoribine-induced expression of IL-12 p40 and IL-12 p70 in B10.S but not SJL/J macrophages. Thus, differences in production of IL-12 p70 due to expression of the p35 subunit and in activity of TLR7, as well as activation of factors downstream of ERK MAP-kinases likely underlie the disparity in innate immunity between SJL/J and B10.S macrophages to TMEV.
authors.affiliation: Department of Oral Biology and Nebraska Center for Virology, University of Nebraska Medical Center, 40th and Holdrege Streets, Lincoln, NE 68583-0740, USA. tpetro@unmc.edu
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Petro
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D018664:Interleukin-12 / Q000096:biosynthesis*; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017945:Theilovirus; D051199:Toll-Like Receptor 7
chemical_list: D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D018664:Interleukin-12; D020928:Mitogen-Activated Protein Kinases