Cutting Edge: Cell Surface Expression and Lipopolysaccharide Signaling Via the Toll-Like Receptor 4-MD-2 Complex on Mouse Peritoneal Macrophages

Akashi, Shigeo; Shimazu, Rintaro; Ogata, Hirotaka; Nagai, Yoshinori; Takeda, Kiyoshi; Kimoto, Masao; Miyake, Kensuke

doi:10.4049/jimmunol.164.7.3471

Cited by 434 publications

(346 citation statements)

References 23 publications

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“…The unique TLR expression pattern, in particular the lack of TLR4 and the associated molecule MD2, suggests that the cervicovaginal epithelium is capable of responding to Gram-negative pathogens in the absence of endotoxin recognition. This is in contrast to the mechanism used by phagocytes (15,17,82), dendritic cells (83), and endothelial cells (51,84), which express TLR4 and are highly sensitive to LPS activation through the Toll/IL-1 signaling pathway.…”

Section: Discussionmentioning

confidence: 79%

Response toNeisseria gonorrhoeaeby Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling

Fichorova

Cronin

Lien

et al. 2002

The Journal of Immunology

211

174

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Toll-like receptors (TLRs) have recently been identified as fundamental components of the innate immune response to bacterial pathogens. We investigated the role of TLR signaling in immune defense of the mucosal epithelial cells of the lower female genital tract. This site provides first line defense against microbial pathogens while remaining tolerant to a complex biosystem of resident microbiota. Epithelial cells derived from normal human vagina, ectocervix, and endocervix expressed mRNA for TLR1, -2, -3, -5, and -6. However, they failed to express TLR4 as well as MD2, two essential components of the receptor complex for LPS in phagocytes and endothelial cells. Consistent with this, endocervical epithelial cells were unresponsive to protein-free preparations of lipooligosaccharide from Neisseria gonorrhoeae and LPS from Escherichia coli. However, they were capable of responding to whole Gram-negative bacteria and bacterial lysates, as demonstrated by NF-κB activation and proinflammatory cytokine production. The presence of soluble CD14, a high-affinity receptor for LPS and other bacterial ligands, enhanced the sensitivity of genital tract epithelial cells to both low and high concentrations of bacteria, suggesting that soluble CD14 can act as a coreceptor for non-TLR4 ligands. These data demonstrate that the response to N. gonorrhoeae and other Gram-negative bacteria at the mucosal surface of the female genital tract occurs in the absence of endotoxin recognition and TLR4-mediated signaling.

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Section: Discussionmentioning

confidence: 79%

Response toNeisseria gonorrhoeaeby Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling

Fichorova

Cronin

Lien

et al. 2002

The Journal of Immunology

211

174

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“…As shown in Fig. 2, around 70% of untreated macrophages were positive for the MoAb MTS 510, a murine antibody that recognized the complex of TLR4 and MD-2 [22]. When cells were stimulated with IL-1b at 50 ng/ml for 24 h, the expression of TLR4 was severely reduced.…”

Section: Il-1b Induces Down-regulation Of Tlr4 On Mouse Peritoneal Mamentioning

confidence: 92%

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Alves-Rosa

Vulcano

Beigier-Bompadre

et al. 2002

Clinical and Experimental Immunology

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SUMMARYEndotoxin or lipopolysaccharide (LPS) tolerance may be partially due to the secretion of potent antiinflammatory cytokines following severe Gram-negative infections, or by low doses of LPS. In this work, we describe the effects of interleukin-1b (IL-1b) and tumour necrosis factor alpha (TNF-a), two early cytokines secreted after LPS exposure, in the induction of LPS tolerance. Our results demonstrate that mice treated with three daily doses of 100 ng of IL-1b were tolerant to LPS-induced shock. However, TNF-a was unable to induce an LPS refractory state. Given the fact that 100 ng of IL-1b increase the plasma levels of glucocorticoids, we evaluated whether a daily injection of dexamethasone (DEX) alone was able to reproduce the LPS-like tolerant state. However, no signs of LPS refractoriness were detected, except when DEX was administered concomitantly with a dose of IL-1b that does not induce corticosterone secretion (12 ng/mouse). This dose was found to induce in vitro up-regulation of the glucocorticoid receptors (GcR) of peritoneal macrophages following 24 h of treatment. In addition, we demonstrate that IL-1b is capable of inducing the down-regulation of Toll-like receptor 4 (TLR4), a crucial molecule in the signal transduction of LPS. Taken together, our results indicate that IL-1b can generate tolerance to LPS in vivo, and suggest that the regulation of mechanisms of the downregulation of TLR4, as well as those involved in the expression of GcR and/or in the secretion of glucocorticoids, would be crucial for these effects.

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“…We investigated the presence of this complex on macrophages derived from Sn, Cr, F1 (Sn × Cr) and transgenic TCr-1 and TCr-5 mice by FCM using a monoclonal anti-TLR4-MD-2 antibody [30]. This antibody recognizes the complex, but neither TLR4 nor MD-2 alone.…”

Section: Expression Of the Tlr4-md-2 Complex On Macrophagesmentioning

confidence: 99%

Toll‐like receptor 4 expression levels determine the degree of LPS‐susceptibility in mice

et al. 2003

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C57BL/10ScCr (Cr) mice carry a deletion of the Toll-like receptor 4 (tlr4) gene (i.e. they are tlr4 0/0 ) and are thus refractory to LPS effects. Insertion of wild-type tlr4 transgene into the tlr4 0/0 Cr germ line endowed LPS susceptibility in the two transgenic lines created, indicating that TLR4 is the only limiting factor for LPS responsiveness in Cr mice. The absolute levels of tlr4 mRNA expressed by the heterozygous transgenic (tlr4 Tr/0 ), wild-type C57BL/10ScSn (Sn) (tlr4 +/+ ) and heterozygous F1 (Sn × Cr) (tlr4 +/0 ) mice varied markedly. However, the pattern of distribution of expression in the different organs was the same in all strains. In different biological assays (B cell mitogenicity, cytokine induction and lethal toxicity) the degree of LPS response obtained in the different strains of mice correlated with the levels of tlr4 mRNA expression. In macrophages, investigation of the LPS-induced cytokine (IL-6) response revealed a linear relationship between the response and the logarithm of TLR4-MD-2 levels.

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Cutting Edge: Cell Surface Expression and Lipopolysaccharide Signaling Via the Toll-Like Receptor 4-MD-2 Complex on Mouse Peritoneal Macrophages

Cited by 434 publications

References 23 publications

Response toNeisseria gonorrhoeaeby Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling

Response toNeisseria gonorrhoeaeby Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Toll‐like receptor 4 expression levels determine the degree of LPS‐susceptibility in mice

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