title: Robust expression of TNF-alpha, IL-1beta, RANTES, and IP-10 by human microglial cells during nonproductive infection with herpes simplex virus.
abstract: Cytokine (TNF-alpha/beta, IL-1beta, IL-6, IL-18, IL-10, and IFN-alpha/beta/gamma) and chemokine (IL-8, IP-10, MCP-1, MIP-1alpha/beta, and RANTES) production during herpes simplex virus (HSV) 1 infection of human brain cells was examined. Primary astrocytes as well as neurons were found to support HSV replication, but neither of these fully permissive cell types produced cytokines or chemokines in response to HSV. In contrast, microglia did not support extensive viral replication; however, ICP4 was detected by immunochemical staining, demonstrating these cells were infected. Late viral protein (nucleocapsid antigen) was detected in <10% of infected microglial cells. Microglia responded to nonpermissive viral infection by producing considerable amounts of TNF-alpha, IL-1beta, IP-10, and RANTES, together with smaller amounts of IL-6, IL-8, and MIP-1alpha as detected by RPA and ELISA. Surprisingly, no interferons (alpha, beta, or gamma) were detected in response to viral infection. Pretreatment of fully permissive astrocytes with TNF-alpha prior to infection with HSV was found to dramatically inhibit replication, resulting in a 14-fold reduction of viral titer. In contrast, pretreatment of astrocytes with IL-1beta had little effect on viral replication. When added to neuronal cultures, exogenous TNF-alpha or IL-1beta did not suppress subsequent HSV replication. Exogenously added IP-10 inhibited HSV replication in neurons (with a 32-fold reduction in viral titer), however, similar IP-10 treatment did not affect viral replication in astrocytes. These results suggest that IP-10 possesses direct antiviral activity in neurons and support a role for microglia in both antiviral defense of the brain as well as amplification of immune responses during neuroinflammation.
authors.affiliation: Neuroimmunology Laboratory, Minneapolis Medical Research Foundation, Minneapolis, Minnesota 55404, USA. loken006@tc.umn.edu
authors.forename: J R
authors.initials: JR
authors.lastname: Lokensgard
authors.forename: S
authors.initials: S
authors.lastname: Hu
authors.forename: W
authors.initials: W
authors.lastname: Sheng
authors.forename: M
authors.initials: M
authors.lastname: vanOijen
authors.forename: D
authors.initials: D
authors.lastname: Cox
authors.forename: M C
authors.initials: MC
authors.lastname: Cheeran
authors.forename: P K
authors.initials: PK
authors.lastname: Peterson
mesh_terms: D001253:Astrocytes / Q000166:cytology / Q000821:virology; D001921:Brain / Q000166:cytology / Q000821:virology; D002070:Butadienes / Q000494:pharmacology; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000276:immunology; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D020803:Encephalitis, Herpes Simplex / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus / Q000166:cytology; D018259:Herpesvirus 1, Human / Q000254:growth & development*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000276:immunology; D017628:Microglia / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D009474:Neurons / Q000166:cytology / Q000821:virology; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D014779:Virus Replication
chemical_list: D002070:Butadienes; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D009570:Nitriles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole