Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound
| Autor: | Silvia Campo, Federica Capolunghi, Claudio Sette, Nicola Fanto, Maria Loiarro, Rita De Santis, Vito Ruggiero, Paolo Carminati, Brunilde Arseni, Grazia Gallo, Rita Carsetti |
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| Rok vydání: | 2007 |
| Předmět: |
Transcription
Genetic Cellular differentiation Interleukin-1beta Plasma Cells Immunology Administration Oral Biology Heterocyclic Compounds 2-Ring Serine Mice Adjuvants Immunologic Biomimetic Materials Interleukin-1 Receptor-Associated Kinases Animals Humans Immunology and Allergy Spiro Compounds Cell Proliferation Inflammation Interleukin-6 Kinase NF-kappa B Receptors Interleukin-1 Signal transducing adaptor protein Cell Differentiation Cell Biology IRAK4 Protein Structure Tertiary Cell biology Oligodeoxyribonucleotides Toll-Like Receptor 9 Chronic Disease Myeloid Differentiation Factor 88 Female Dimerization Oligopeptides Intracellular HeLa Cells |
| Zdroj: | Journal of Leukocyte Biology. 82:801-810 |
| ISSN: | 1938-3673 0741-5400 |
| DOI: | 10.1189/jlb.1206746 |
| Popis: | MyD88 is an adaptor protein, which plays an essential role in the intracellular signaling elicited by IL-1R and several TLRs. Central to its function is the ability of its Toll/IL-1R translation initiation region (TIR) domain to heterodimerize with the receptor and to homodimerize with another MyD88 molecule to favor the recruitment of downstream signaling molecules such as the serine/threonine kinases IL-1R-associated kinase 1 (IRAK1) and IRAK4. Herein, we have synthesized and tested the activity of a synthetic peptido-mimetic compound (ST2825) modeled after the structure of a heptapeptide in the BB-loop of the MyD88-tIR domain, which interferes with MyD88 signaling. ST2825 inhibited MyD88 dimerization in coimmunoprecipitation experiments. This effect was specific for homodimerization of the TIR domains and did not affect homodimerization of the death domains. Moreover, ST2825 interfered with recruitment of IRAK1 and IRAK4 by MyD88, causing inhibition of IL-1β-mediated activation of NF-κB transcriptional activity. After oral administration, ST2825 dose-dependently inhibited IL-1β-induced production of IL-6 in treated mice. Finally, we observed that ST2825 suppressed B cell proliferation and differentiation into plasma cells in response to CpG-induced activation of TLR9, a receptor that requires MyD88 for intracellular signaling. Our results indicate that ST2825 blocks IL-1R/TLR signaling by interfering with MyD88 homodimerization and suggest that it may have therapeutic potential in treatment of chronic inflammatory diseases. |
| Databáze: | OpenAIRE |
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