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Dependence of pathogen molecule-induced Toll-like receptor activation and cell function on Neu1 sialidase

(2009) GLYCOCONJUGATE JOURNAL. 26(9). p.1197-1212
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Abstract
The signaling pathways of mammalian Toll-like receptors (TLR) are well characterized, but the initial molecular mechanisms activated following ligand interactions with the receptors remain poorly defined. Here, we show a membrane controlling mechanism that is initiated by ligand binding to TLR-2, -3 and-4 to induce Neu1 sialidase activity within minutes in live primary bone marrow (BM) macrophage cells and macrophage and dendritic cell lines. Central to this process is that Neu1 and not Neu2,-3 and-4 forms a complex with TLR-2,-3 and-4 on the cell surface of na < ve macrophage cells. Neuraminidase inhibitors BCX1827, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), zanamivir and oseltamivir carboxylate have a limited significant inhibition of the LPS-induced sialidase activity in live BMC-2 macrophage cells but Tamiflu (oseltamivir phosphate) completely blocks this activity. Tamiflu inhibits LPS-induced sialidase activity in live BMC-2 cells with an IC50 of 1.2 mu M compared to an IC50 of 1015 mu M for its hydrolytic metabolite oseltamivir carboxylate. Tamiflu blockage of LPS-induced Neu1 sialidase activity is not affected in BMC-2 cells pretreated with anticarboxylesterase agent clopidogrel. Endotoxin LPS binding to TLR4 induces Neu1 with subsequent activation of NF kappa B and the production of nitric oxide and pro-inflammatory IL-6 and TNF alpha cytokines in primary and macrophage cell lines. Hypomorphic cathepsin A mice with a secondary Neu1 deficiency respond poorly to LPS-induced pro-inflammatory cytokines compared to the wild-type or hypomorphic cathepsin A with normal Neu1 mice. Our findings establish an unprecedented mechanism for pathogen molecule-induced TLR activation and cell function, which is critically dependent on Neu1 sialidase activity associated with TLR ligand treated live primary macrophage cells and macrophage and dendritic cell lines.
Keywords
MACROPHAGES, COMPLEX, OSELTAMIVIR, GLYCOSYLATION, Neu1 deficient mice, pro-inflammatory cytokines, NF kappa B activation, Neu1 sialidase, Toll-like receptors, CLASS-I, T-LYMPHOCYTES, EXOGENOUS ANTIGENS, DENDRITIC CELLS, EXPRESSION, MICE

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Citation

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Chicago
Amith, Schammim Ray, Preethi Jayanth, Susan Franchuk, Sarah Siddiqui, Volkan Seyrantepe, Katrina Gee, Sameh Basta, Rudi Beyaert, Alexey V Pshezhetsky, and Myron R Szewczuk. 2009. “Dependence of Pathogen Molecule-induced Toll-like Receptor Activation and Cell Function on Neu1 Sialidase.” Glycoconjugate Journal 26 (9): 1197–1212.
APA
Amith, S. R., Jayanth, P., Franchuk, S., Siddiqui, S., Seyrantepe, V., Gee, K., Basta, S., et al. (2009). Dependence of pathogen molecule-induced Toll-like receptor activation and cell function on Neu1 sialidase. GLYCOCONJUGATE JOURNAL, 26(9), 1197–1212.
Vancouver
1.
Amith SR, Jayanth P, Franchuk S, Siddiqui S, Seyrantepe V, Gee K, et al. Dependence of pathogen molecule-induced Toll-like receptor activation and cell function on Neu1 sialidase. GLYCOCONJUGATE JOURNAL. 2009;26(9):1197–212.
MLA
Amith, Schammim Ray, Preethi Jayanth, Susan Franchuk, et al. “Dependence of Pathogen Molecule-induced Toll-like Receptor Activation and Cell Function on Neu1 Sialidase.” GLYCOCONJUGATE JOURNAL 26.9 (2009): 1197–1212. Print.
@article{818088,
  abstract     = {The signaling pathways of mammalian Toll-like receptors (TLR) are well characterized, but the initial molecular mechanisms activated following ligand interactions with the receptors remain poorly defined. Here, we show a membrane controlling mechanism that is initiated by ligand binding to TLR-2, -3 and-4 to induce Neu1 sialidase activity within minutes in live primary bone marrow (BM) macrophage cells and macrophage and dendritic cell lines. Central to this process is that Neu1 and not Neu2,-3 and-4 forms a complex with TLR-2,-3 and-4 on the cell surface of na {\textlangle} ve macrophage cells. Neuraminidase inhibitors BCX1827, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), zanamivir and oseltamivir carboxylate have a limited significant inhibition of the LPS-induced sialidase activity in live BMC-2 macrophage cells but Tamiflu (oseltamivir phosphate) completely blocks this activity. Tamiflu inhibits LPS-induced sialidase activity in live BMC-2 cells with an IC50 of 1.2 mu M compared to an IC50 of 1015 mu M for its hydrolytic metabolite oseltamivir carboxylate. Tamiflu blockage of LPS-induced Neu1 sialidase activity is not affected in BMC-2 cells pretreated with anticarboxylesterase agent clopidogrel. Endotoxin LPS binding to TLR4 induces Neu1 with subsequent activation of NF kappa B and the production of nitric oxide and pro-inflammatory IL-6 and TNF alpha cytokines in primary and macrophage cell lines. Hypomorphic cathepsin A mice with a secondary Neu1 deficiency respond poorly to LPS-induced pro-inflammatory cytokines compared to the wild-type or hypomorphic cathepsin A with normal Neu1 mice. Our findings establish an unprecedented mechanism for pathogen molecule-induced TLR activation and cell function, which is critically dependent on Neu1 sialidase activity associated with TLR ligand treated live primary macrophage cells and macrophage and dendritic cell lines.},
  author       = {Amith, Schammim Ray and Jayanth, Preethi and Franchuk, Susan and Siddiqui, Sarah and Seyrantepe, Volkan and Gee, Katrina and Basta, Sameh and Beyaert, Rudi and Pshezhetsky, Alexey V and Szewczuk, Myron R},
  issn         = {0282-0080},
  journal      = {GLYCOCONJUGATE JOURNAL},
  keyword      = {MACROPHAGES,COMPLEX,OSELTAMIVIR,GLYCOSYLATION,Neu1 deficient mice,pro-inflammatory cytokines,NF kappa B activation,Neu1 sialidase,Toll-like receptors,CLASS-I,T-LYMPHOCYTES,EXOGENOUS ANTIGENS,DENDRITIC CELLS,EXPRESSION,MICE},
  language     = {eng},
  number       = {9},
  pages        = {1197--1212},
  title        = {Dependence of pathogen molecule-induced Toll-like receptor activation and cell function on Neu1 sialidase},
  url          = {http://dx.doi.org/10.1007/s10719-009-9239-8},
  volume       = {26},
  year         = {2009},
}

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