The Lip Lipoprotein from Neisseria gonorrhoeae Stimulates Cytokine Release and NF-κB Activation in Epithelial Cells in a Toll-like Receptor 2-dependent Manner

Fisette, Philip L.; Ram, Sanjay; Andersen, Jardar; Guo, Wen; Ingalls, Robin R.

doi:10.1074/jbc.m306587200

Cited by 96 publications

(90 citation statements)

References 50 publications

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“…Neissera gonorrhoeae, Chlamydia trichomatis and Candida, the respective etiological agents of gonorrhea, chlamydia and candidiasis, can stimulate cells via TLR2 (Fisette et al, 2003;Deva et al, 2003;Darville et al, 2003). The stimulatory capacity of either normal or BV CVLs is not attributable to these agents since all subjects were negative for these infections.…”

Section: Discussionmentioning

confidence: 99%

TLR2-Mediated Cell Stimulation in Bacterial Vaginosis

Mares¹,

Simões²,

Novak³

et al. 2008

Journal of Lower Genital Tract Disease

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Bacterial vaginosis (BV) is associated with preterm labor, pelvic inflammatory disease and increased HIV acquisition, although the pathways that mediate these pathological effects have not been elucidated. To determine the presence of toll-like receptor (TLR)-ligands and their specificity in BV, genital tract fluids were collected from women with and without BV by cervicovaginal lavage (CVL). The CVL samples were evaluated for their ability to stimulate secretion of proinflammatory cytokines and to activate NF κB and the HIV long terminal repeat (LTR), indicators of TLR activation, in human monocytic cells. Stimulation with BV CVLs induced higher levels of IL-8 and TNFα secretion, as well as higher levels of HIV LTR and NF κB activation, than CVLs from women with normal healthy bacterial flora. To identify which TLRs were important in BV, 293 cells expressing specific TLRs were exposed to CVL samples. BV CVLs induced higher IL-8 secretion by cells expressing TLR2 than CVLs from women without BV. Surprisingly, BV CVLs did not stimulate cells expressing TLR4/MD2, although these cells responded to purified LPS, a TLR4 ligand. BV CVLs, in cells expressing TLR2, also activated the HIV LTR. Thus, these studies show that soluble factor(s) present in the lower genital tract of women with BV activate cells via TLR2, identifying a pathway through which BV may mediate adverse effects.

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Section: Discussionmentioning

confidence: 99%

TLR2-Mediated Cell Stimulation in Bacterial Vaginosis

Mares¹,

Simões²,

Novak³

et al. 2008

Journal of Lower Genital Tract Disease

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“…Our previous work and that of other investigators has shown that gonococci can initiate proinflammatory cytokine expression through activation of NFκB. In particular, gonococci engage innate immune receptors TLR4 and TLR2 with lipooligosaccharide (LOS) engaging TLR4, and PorB and lipoprotein Lip functioning as agonists for TLR2 (7)(8)(9). In urogenital epithelial cell lines, gonococcal infection induces upregulation of a variety of proinflammatory and inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-8 (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

TREM-2 binds to lipooligosaccharides of Neisseria gonorrhoeae and is expressed on reproductive tract epithelial cells

et al. 2008

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Triggering receptor expressed on myeloid cells-2 (TREM-2) is an innate immune receptor that initiates cellular activation upon ligation. In this study, we examined the interaction of TREM-2 with Neisseria gonorrhoeae using murine TREM-2A as it has been reported to recognize bacterial ligands. Using a whole bacteria ELISA, TREM-2A bound to all 6 strains in variable degrees. Far western blots of gonococcal outer membranes revealed TREM-2A binding to lipooligosaccharide (LOS) and Opa protein with predominant binding to LOS. Binding of TREM-2A to LOS was confirmed by ELISA and surface plasmon resonance. O-deacylation of the lipid A significantly reduced binding. Flow cytometry and reporter cell assays showed that gonococci bound to TREM-2A-transfected cells and induced transmembrane signaling. In humans, TREM-2 was constitutively expressed by genitourinary and fallopian tube epithelial cells, both of which are primary targets of gonococcal invasion. Ligation of TREM-2 by LOS induced IL-6 production in HeLa cervical carcinoma cells. To our knowledge, this is the first report of the expression of human TREM-2 by cells deriving from a non-myeloid lineage. We conclude that gonococci can interact with TREM-2 receptors through binding to LOS and Opa protein and initiate cell signaling and cytokine production.

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“…Since TNF-α enhances HIV-1 replication in T cells and macrophages by activation of the NF-κB (26,27), we investigated whether bacteria or TLR agonists induce the proinflammatory cytokine TNF-α. We incubated skin and vaginal biopsies from epithelial tissue with TLR agonists, heat-killed Candida albicans and Neisseria gonorrhea, since these pathogens have been associated with reproductive tract infections (28,29). After 24 hours supernatant was harvested and TNF-α production was analyzed.…”

Section: An Ex Vivo Model To Determine the Effect Of Coinfection On Hmentioning

confidence: 99%

TNF-α and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo

Jong

Witte²,

Oudhoff³

et al. 2008

J. Clin. Invest.

119

189

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The Lip Lipoprotein from Neisseria gonorrhoeae Stimulates Cytokine Release and NF-κB Activation in Epithelial Cells in a Toll-like Receptor 2-dependent Manner

Cited by 96 publications

References 50 publications

TLR2-Mediated Cell Stimulation in Bacterial Vaginosis

TLR2-Mediated Cell Stimulation in Bacterial Vaginosis

TREM-2 binds to lipooligosaccharides of Neisseria gonorrhoeae and is expressed on reproductive tract epithelial cells

TNF-α and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo

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