| First Author | Li J | Year | 2018 |
| Journal | J Immunol | Volume | 200 |
| Issue | 12 | Pages | 4036-4043 |
| PubMed ID | 29728508 | Mgi Jnum | J:263319 |
| Mgi Id | MGI:6164082 | Doi | 10.4049/jimmunol.1700693 |
| Citation | Li J, et al. (2018) Small Molecule Mimetics of alpha-Helical Domain of IRAK2 Attenuate the Proinflammatory Effects of IL-33 in Asthma-like Mouse Models. J Immunol 200(12):4036-4043 |
| abstractText | IL-33 and its receptor ST2 play important roles in airway inflammation and contribute to asthma onset and exacerbation. The IL-33/ST2 signaling pathway recruits adapter protein myeloid differentiation primary response 88 (MyD88) to transduce intracellular signaling. MyD88 forms a complex with IL-R-associated kinases (IRAKs), IRAK4 and IRAK2, called the Myddosome (MyD88-IRAK4-IRAK2). The myddosome subsequently activates downstream NF-kappaB and MAPKs p38 and JNK. We established an asthma-like mouse model by intratracheal administration of IL-33. The IL-33 model has a very similar phenotype compared with the OVA-induced mouse asthma model. The importance of MyD88 in the IL-33/ST2 signaling transduction was demonstrated by the MyD88 knockout mice, which were protected from the IL-33-induced asthma. We synthesized small molecule mimetics of the alpha-helical domain of IRAK2 with drug-like characteristics based on the recent advances in the designing of alpha-helix compounds. The mimetics can competitively interfere in the protein-protein interaction between IRAK2 and IRAK4, leading to disruption of Myddosome formation. A series of small molecules were screened using an NF-kappaB promoter assay in vitro. The lead compound, 7004, was further studied in the IL-33-induced and OVA-induced asthma mouse models in vivo. Compound 7004 can inhibit the IL-33-induced NF-kappaB activity, disrupt Myddosome formation, and attenuate the proinflammatory effects in asthma-like models. Our data indicate that the Myddosome may represent a novel intracellular therapeutic target for diseases in which IL-33/ST2 plays important roles, such as asthma and other inflammatory diseases. |
