title: Tumor necrosis factor-alpha (TNF-alpha) regulates Toll-like receptor 2 (TLR2) expression in microglia.
abstract: Microglia represent one effector arm of CNS innate immunity as evident by their role in pathogen recognition. We previously reported that exposure of microglia to Staphylococcus aureus (S. aureus), a prevalent CNS pathogen, led to elevated Toll-like receptor 2 (TLR2) expression, a pattern recognition receptor capable of recognizing conserved structural motifs associated with gram-positive bacteria such as S. aureus. In this study, we demonstrate that the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) enhances TLR2 expression in microglia, whereas interleukin-1beta has no significant effect. To determine the downstream signaling events responsible for elevated microglial TLR2 expression in response to TNF-alpha, a series of signal transduction inhibitors were employed. Treatment with caffeic acid phenethyl ester, an inhibitor of redox-mediated nuclear factor-kappa B activation, significantly attenuated TNF-alpha-induced TLR2 expression. Similar results were observed with the IKK-2 and IkappaB-alpha inhibitors SC-514 and BAY 11-7082, respectively. In contrast, no significant alterations in TLR2 expression were observed with protein kinase C or p38 mitogen-activated protein kinase inhibitors. A definitive role for TNF-alpha was demonstrated by the inability of S. aureus to augment TLR2 expression in microglia isolated from TNF-alpha knockout mice. In addition, TLR2 expression was significantly attenuated in brain abscesses of TNF-alpha knockout mice. Collectively, these results indicate that in response to S. aureus, TNF-alpha acts in an autocrine/paracrine manner to enhance TLR2 expression in microglia and that this effect is mediated, in part, by activation of the nuclear factor-kappa B pathway.
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Mohsin Md
authors.initials: MM
authors.lastname: Syed
authors.forename: Nirmal K
authors.initials: NK
authors.lastname: Phulwani
authors.forename: Tammy
authors.initials: T
authors.lastname: Kielian
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology*; D018836:Inflammation Mediators / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000382:microbiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013211:Staphylococcus aureus / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D016328:NF-kappa B; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha