Shared Actions of Endotoxin and Taxol on TNF Receptors and TNF release

Ding, Aihao; Porteu, Françoise; Sánchez, Elizabeth; Nathan, Carl

doi:10.1126/science.1970196

Cited by 281 publications

(209 citation statements)

References 18 publications

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“…Results of this study demonstrated that paclitaxel in this range of concentrations activated IL-6 through the activation of JNK signaling pathway but not through the LPS-like activity of paclitaxel. First, the 1 mM concentration of paclitaxel used in this study was much lower than that reportedly (3-140 mM) effective for upregulation of IL1alpha, IL-1 beta, IL-8 and TNF-alpha (Ding et al, 1990;Lee et al, 1996;Lanni et al, 1997;Kawasaki et al, 2000Kawasaki et al, , 2003Perera et al, 2001;Takeda et al, 2003). Second, no upregulation of TLR4, MyD88, or NF-IL6 in terms of mRNA levels in BR cells treated with 1 mM paclitaxel was noted (Figure 6a).…”

Section: Discussionmentioning

confidence: 60%

“…At high concentrations (5-30 mM), paclitaxel has been reported to exert endotoxin LPS-like effects through treatment on macrophage-like cells, including the upregulation of various cytokines (Ding et al, 1990;Lee et al, 1996;Lanni et al, 1997). Lipopolysaccharidelike effects of paclitaxel were thought to be conveyed through TNF receptor (Ding et al, 1990) or TLR-4 (Kawasaki et al, 2000(Kawasaki et al, , 2003Perera et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Lipopolysaccharidelike effects of paclitaxel were thought to be conveyed through TNF receptor (Ding et al, 1990) or TLR-4 (Kawasaki et al, 2000(Kawasaki et al, , 2003Perera et al, 2001). Microtubule cytoskeleton dysfunction has been shown to activate NF-kB (Rosette and Karin, 1995; Das and Mechanisms of IL-6 upregulation by paclitaxel T-H Wang et al White, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Treatment of macrophage-like cells with high concentrations (5-30 mM) of paclitaxel has been reported to exert endotoxin lipopolysaccharide (LPS)-like effects, including the upregulation of various cytokines (Ding et al, 1990;Lee et al, 1996;Lanni et al, 1997). More recently, Toll-like receptor 4 (TLR4) on murine macrophage has been shown to be the receptor for paclitaxel (Kawasaki et al, 2000(Kawasaki et al, , 2003Perera et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

Chan

Chen

et al. 2006

Oncogene

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Paclitaxel (Taxol) is an antineoplastic agent that specifically targets microtubules and arrests cells at the G2/M phase of the cell cycle. In addition to mitotic arrest, the activation of c-Jun N-terminal kinase (JNK) signaling pathway has been demonstrated to be involved in the process leading to apoptosis. In an attempt to explore what genes are transcriptionally regulated by the activated JNK signaling pathway upon paclitaxel treatment, we used cDNA microarrays to analyse the changes of gene expression in human ovarian cancer cells that were treated with paclitaxel and/or the JNK inhibitor SP600125. Among 20 genes that were specifically regulated by the paclitaxel-activated JNK pathway, interleukin (IL)-6 was shown to elicit function through the JAK-STAT signaling pathway in an autocrine and/or paracrine fashion. Subsequently, we identified that 87.5% of eight tested ovarian cancer lines secreted detectable levels of IL-6, which could be further upregulated 2-3.2 fold by 1 lM paclitaxel. Dissection on regulatory pathways for IL-6 indicated that (i) when ovarian cancer cells were treated with paclitaxel at low but clinically achievable concentrations (exemplified by 1 lM in this study), the JNK signaling pathway was the major stimulator of IL-6 gene regulation and (ii) at suprapharmacologically high concentrations (exemplified by 50 lM), paclitaxel exerted lipopolysaccharide-like effects, most likely through the Toll-like receptor 4 signaling pathway. Collectively, these results suggest that paclitaxel upregulates functional IL-6 expression in human ovarian cancer cells through multiple signaling pathways.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

Chan

Chen

et al. 2006

Oncogene

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“…Furthermore, a Chinese hamster ovary cell line carrying a mutation in MD-2, in which Tyr was substituted for Cys 95 , abrogated LPS-induced signaling (13). In addition to conferring LPS responsiveness, coexpression of MD-2 and TLR4 is required for conferring responsiveness to anti-mitotic compound Taxol (14), which has long been observed to mimic LPS in mouse cells (15,16).…”

Section: Identification Of Mouse Md-2 Residues Important Formentioning

confidence: 99%

Identification of Mouse MD-2 Residues Important for Forming the Cell Surface TLR4-MD-2 Complex Recognized by Anti-TLR4-MD-2 Antibodies, and for Conferring LPS and Taxol Responsiveness on Mouse TLR4 by Alanine-Scanning Mutagenesis

Kawasaki

Nogawa

Nishijima

2003

The Journal of Immunology

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The expression of MD-2, which associates with Toll-like receptor (TLR) 4 on the cell surface, confers LPS and LPS-mimetic Taxol responsiveness on TLR4. Alanine-scanning mutagenesis was performed to identify the mouse MD-2 residues important for conferring LPS and Taxol responsiveness on mouse TLR4, and for forming the cell surface TLR4-MD-2 complex recognized by anti-TLR4-MD-2 Ab MTS510. Single alanine mutations were introduced into mouse MD-2 (residues 17–160), and the mutants were expressed in a human cell line expressing mouse TLR4. Mouse MD-2 mutants, in which a single alanine mutation was introduced at Cys37, Leu71, Leu78, Cys95, Tyr102, Cys105, Glu111, Val113, Ile117, Pro118, Phe119, Glu136, Ile138, Leu146, Cys148, or Thr152, showed dramatically reduced ability to form the cell surface mouse TLR4-mouse MD-2 complex recognized by MTS510, and the mutants also showed reduced ability to confer LPS and Taxol responsiveness. In contrast, mouse MD-2 mutants, in which a single alanine mutation was introduced at Tyr34, Tyr36, Gly59, Val82, Ile85, Phe126, Pro127, Gly129, Ile153, Ile154, and His155 showed normal ability to form the cell surface mouse TLR4-mouse MD-2 complex recognized by MTS510, but their ability to confer LPS and Taxol responsiveness was apparently reduced. These results suggest that the ability of MD-2 to form the cell surface mouse TLR4-mouse MD-2 complex recognized by MTS510 is essential for conferring LPS and Taxol responsiveness on TLR4, but not sufficient. In addition, the required residues at codon numbers 34, 85, 101, 122, and 153 for the ability of mouse MD-2 to confer LPS responsiveness are partly different from those for Taxol responsiveness.

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