Genetic and Physical Mapping of theLpsLocus: Identification of the Toll-4 Receptor as a Candidate Gene in the Critical Region

Poltorak, A.; Smirnova, I.; He, Xiaoming; Liu, M. Y.; Huffel, Christophe Van; Birdwell, Dale; Alejos, E.; Silva, M.; Du, Xuhua; Thompson, Peter; Chan, Edmund; Ledesma, Jessica; Clifton, Sandra W.; Vogel, Siegfried; Beutler, Bruce

doi:10.1006/bcmd.1999.0230

Cited by 57 publications

(61 citation statements)

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“…Expression of TNF mRNA (C) was measured 4 h after treatment by real‐time PCR analysis. Production of TNF was measured 9 h after treatments using bioassay as described previously (Poltorak et al ., 1998). Data are expressed as means ± SD of three independent experiments.…”

Section: Resultsmentioning

confidence: 99%

“…D. THP‐1 cells were treated with LPS (100 ng ml −1 ) with or without various concentrations of recombinant human G‐CSF in THP‐1 cells. Production of TNF was measured 9 h after LPS‐treatment as described previously (Poltorak et al ., 1998). Data are expressed as means ± SD of three independent experiments.…”

Section: Resultsmentioning

confidence: 99%

“…Standard curves for each cytokine were generated using purified recombinant proteins of known concentration provided by the manufacturer. TNF bioassays were used to measure TNF production as previously described (Poltorak et al ., 1998).…”

Section: Methodsmentioning

confidence: 99%

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G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus-induced suppression of TNF production in macrophages

et al. 2006

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SummaryLactobacillus rhamnosus is a human commensal with known immunomodulatory properties. To date the mechanism of these immunomodulatory effects is not well understood. To unravel the immunomodulatory signalling mechanism, we investigated the effects of two strains of L. rhamnosus , L. rhamnosus GG and GR-1, in modulating production of tumour necrosis factor-a (TNF) in human monocytic cell line THP-1 and mouse macrophages. Live L. rhamnosus GG and GR-1 or their spent culture supernatant induced minuscule amounts of TNF production but large quantities of granulocyte-colony stimulating factor (G-CSF) in macrophages compared with those induced by pathogenic Escherichia coli GR-12 and Enterococcus faecalis . By using neutralizing antibodies and G-CSF receptor knockout mice, we demonstrated that G-CSF secreted from L. rhamnosus GG-and GR-1-exposed macrophages suppressed TNF production induced by E. coli -or lipopolysaccharide-activated macrophages through a paracrine route. The suppression of TNF production by G-CSF was mediated through activation of STAT3 and subsequent inhibition of c-Jun-N-terminal kinases (JNKs). The inhibition of JNK activation required STAT3 a -mediated de novo protein synthesis. This demonstrates a novel role of G-CSF in L. rhamnosus -triggered anti-inflammatory effects and its mechanism in the suppression of TNF production in macrophages.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus-induced suppression of TNF production in macrophages

et al. 2006

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“…As CD‐14 is a membrane‐anchored protein lacking intracellular domain, it raises a speculation that the LPS action may require a second transmembrane receptor activating the intracellular signalling. Such a receptor has recently been identified to be Toll‐like receptor 4 (TLR4) (Poltorak et al. 1998a,b, Qureshi et al.…”

Section: Regulation By Lipopolysaccharidementioning

confidence: 99%

Regulation of cyclooxygenase‐2 in renal medulla

Yang¹

2003

Acta Physiologica Scandinavica

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Renal medulla is a major site for production and action of prostaglandins (PGs). The renal medullary functions as well as structural integrity are in part dependent on PGs under certain physiological or pathophysiological conditions. The two COX isoforms, COX-1 (constitutive form) and COX-2 (inducible form) are both abundantly expressed in renal inner medulla at basal state, raising a question of which COX isoform may mediate the known functions of PGs in the region. As in many other cell types, COX-1 expression in renal medulla is unlikely subject to robust regulation. In contrast, COX-2 expression in renal medulla is markedly stimulated by chronic salt loading, dehydration and endotoxaemia in vivo. At cellular levels, the signalling pathways responsible for the COX-2 stimulation in renal medullary cells seem to involve both the mitogen-activated protein kinases and NF-kappa B. It is likely that in response to various insults that are detrimental to renal medulla, the induction of PG synthesis may become more dependent on COX-2 than COX-1, and this phenomenon may be relevant to the cytoprotective response against the insults.

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“…Toll‐like receptors (TLRs) detect a variety of microbial structures and initiate protective innate immune responses 1, 2 from the cell surface (TLR1, TLR2, TLR4, TLR5, TLR6) 3–6 and endosomes (TLR3, TLR7, TLR8, and TLR9) 7–9. Nucleic acids are universally conserved and detected by endosomal TLRs.…”

Section: Introductionmentioning

confidence: 99%

Negative regulation of signaling by a soluble form of toll‐like receptor 9

et al. 2011

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SUMMARY Nucleic acids structures are highly conserved through evolution and when self nucleic acids are aberrantly detected by Toll-Like Receptors (TLRs) they contribute to autoimmune disease. For this reason, multiple regulatory mechanisms exist to prevent response to self nucleic acids. TLR9 is a nucleic acid sensing TLR that is regulated at multiple levels including association with accessory proteins, intracellular localization and proteolytic processing. In the endolysosomal compartment TLR9 is proteolytically processed to an 80 kilodalton form (p80) and this processing is a prerequisite for activation. Here we identified a soluble form of TLR9 generated by a novel proteolytic event that cleaved TLR9 between amino acids 724–735. Similar to p80, sTLR9 was generated in endosomes. However, generation of sTLR9 was independent of the cysteine protease cathepsin B active at acidic pH, but partially dependent on cathepsin S, a protease active at neutral pH. Most importantly, sTLR9 inhibited TLR9-dependent signaling. Together, these data support a model where an intrinsic proteolytic processing mechanism negatively regulates TLR9 signaling. Proper balance between the independent proteolytic events likely contributes to regulation of TLR9 mediated innate immunity and prevention of autoimmune disease.

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Genetic and Physical Mapping of theLpsLocus: Identification of the Toll-4 Receptor as a Candidate Gene in the Critical Region

Cited by 57 publications

References 0 publications

G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus-induced suppression of TNF production in macrophages

G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus-induced suppression of TNF production in macrophages

Regulation of cyclooxygenase‐2 in renal medulla

Negative regulation of signaling by a soluble form of toll‐like receptor 9

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