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AvtorAvbelj, Monika, 1985-
Horvat, Simon
Jerala, Roman
Naslov The role of intermediary domain of MyD88 in cell activation and therapeutic inhibition of TLRs / Monika Avbelj, Simon Horvat and Roman Jerala
Vrsta/vsebinatype of material članek - sestavni del
Fizični opisstr. 2394-2404
OpombeAdaptor MyD88 has a pivotal role in TLR and IL-1R signaling and is involved inmediating excercissive inflammation. MyD88 is composed of a death domain anda Toll/IL-1R domain connected by an intermediary domain (INT). The alternatively spliced form of MyD88 lacking the INT prevents signaling through MyD88-dependent TLRs. We designed a peptide from the INT and showed that it inhibits TLR4 activation by LPS when linked to a cell-penetrating peptide. As a new approach for the delivery of signaling-inhibitory peptides, INT peptide cylation also provided efficient cell translocation and inhibition of activation. We determined that INT peptide targets Il-1R-associated kinase.4. Furthermore, MyD88 mutant and molecular modeling refines the MyD88-IL-1R-associated kinase 4 interaction model based on the Myddosome structure. In addition to TLR4, INT peptide also inhibited TLR5, TLR2, TLR9, and IL-1R signaling but not TLR3, which uses Toll/IL-1R domani-containing adapter inducing IFN-ß signaling adaptor. Inhibition of signaling in murine and human cells was observed by decreased NF-kB activation, cytokine mRNA synthesis, and phosphorylation of downstream kinases. In the endotoxemic mouse model, INT peptide suppressed production of inflammatory cytokines and improved survival, supporting therapeutic application of INT peptides for the suppresion of inflammatory conditions mediated by MyD88.
Predmetne oznake (nekontrolirane)imunologija / molekularna genetika
Glej publikacijo TI=The journal of immunology ISSN: 0022-1767.- Vol. 187, no. 5 (2011), str. 2394-2404

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