A lipopolysaccharide-deficient mutant of Neisseria meningitidis elicits attenuated cytokine release by human macrophages and signals via Toll-like receptor (TLR) 2 but not via TLR4/MD2

被引:123
作者
Pridmore, AC
Wyllie, DH
Abdillahi, F
Steeghs, L
van der Ley, P
Dower, SK
Read, RC [1 ]
机构
[1] Univ Sheffield, Royal Hallamshire Hosp, Div Med & Mol Genet, Sheffield S10 2RX, S Yorkshire, England
[2] Natl Inst Publ Hlth & Environm, Lab Vaccine Res, NL-3720 BA Bilthoven, Netherlands
基金
英国惠康基金;
关键词
D O I
10.1086/317647
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Meningococcal disease severity correlates with circulating concentrations of lipopolysaccharide (LPS) and proinflammatory cytokines. Disruption of the lpxA gene of Neisseria meningitidis generated a viable strain that was deficient of detectable LPS. The potency of wild-type N. meningitidis to elicit tumor necrosis factor (TNF)-alpha production by human monocyte-derived macrophages was similar to 10-fold greater than that of the lpxA mutant. Killed wild-type N. meningitidis and its soluble products induced interleukin (IL)-8 and TNF-alpha secretion by transfected HeLa cells expressing Toll-like receptor (TLR) 4/MD2, but the lpxA mutant was inactive via this pathway. In contrast, both strains induced IL-8 promoter activity in TLR2-transfected HeLa cells. These data provide evidence that N. meningitidis contains components other than LPS that can elicit biological responses via pathways that are independent of the TLR4/MD2 receptor system, and TLR2 is one of these alternate pathways. These findings have implications for future therapeutic strategies against meningococcal disease on the basis of the blockade of TLRs and the modulation of LPS activity.
引用
收藏
页码:89 / 96
页数:8
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