期刊
JOURNAL OF NEUROCHEMISTRY
卷 103, 期 4, 页码 1461-1471出版社
WILEY
DOI: 10.1111/j.1471-4159.2007.04838.x
关键词
microglia; nuclear factor-kappa B; Toll-like receptor 2; tumor necrosis factor-alpha
资金
- NCRR NIH HHS [S10 RR19395, S10 RR019395, P20 RR6460, S10 RR019395-01A1] Funding Source: Medline
- NIMH NIH HHS [R01 MH065297, R01 MH65297, R01 MH065297-04] Funding Source: Medline
- NINDS NIH HHS [R01 NS055385, R01 NS055385-05A2, P30 NS047546-03, NS055385, P30 NS047546-02, P30 NS047546, P30 NS047546-04] Funding Source: Medline
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-1 beta 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 I kappa B-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.
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