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Issue 89, 2014
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Molecular mechanism of action of K(D)PT as an IL-1RI antagonist for the treatment of rhinitis

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Abstract

Background: Interleukin-1 receptor type I (IL-1RI) is critical for both innate immunity and inflammation. IL-1RI stimulates thymocyte proliferation and the release of several interleukin cytokines. These properties have increased interest in targeting IL-1RI for the treatment of inflammatory diseases. Here, an IL-1RI antagonist, K(D)PT (Lys-D-Pro-Thr), was tested in an allergic rhinitis model. The mechanism of action was then investigated. Methods: HEK293/IL-1RI cells and an allergic rhinitis animal model were treated with K(D)PT to evaluate its therapeutic effects. Fifty nanosecond (ns) molecular dynamic (MD) simulations were performed on the K(D)PT/IL-1RI complex, unliganded IL-1RI, and the IL-1β/IL-1RI complex to explore the mechanism of action of K(D)PT. Results: K(D)PT down-regulated the IL-1RI-mediated induction of IL-2 and IL-4 mRNA expression by IL-1β in HEK293/IL-1RI cells. In addition, nose itching was alleviated in mice treated with K(D)PT. Serum levels of IL-2 and IL-4 as well as eosinophil infiltration were also reduced. The data suggested that IL-1RI was highly expressed in the nasal mucosa of mice with allergic rhinitis. MD simulations revealed the following: (1) IL-1RI remains in the open conformation in the IL-1RI/IL-1β complex; (2) in unliganded IL-1RI, domains I and III randomly moved closer and apart without any significant energetic changes; (3) K(D)PT locks the C- and N- terminals of IL-1RI by forming hydrogen bonds with both terminals to adopt a closed conformation and consequently minimizes the system energy. Conclusions: IL-1RI antagonist K(D)PT effectively treated allergic rhinitis. The molecular mechanism of action indicated that K(D)PT connects the C- and N- terminals of IL-1RI via hydrogen bond formation to establish a stable conformation and consequently minimize the system energy of IL-1RI.

Graphical abstract: Molecular mechanism of action of K(D)PT as an IL-1RI antagonist for the treatment of rhinitis

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Article information


Submitted
21 Aug 2014
Accepted
24 Sep 2014
First published
24 Sep 2014

RSC Adv., 2014,4, 48741-48749
Article type
Paper
Author version available

Molecular mechanism of action of K(D)PT as an IL-1RI antagonist for the treatment of rhinitis

C. Li, H. Ge, L. Cui, Y. Li, B. Cheng, G. Zhang, Z. Zhang, H. Qi, Y. Ruan, Q. Gu and J. Xu, RSC Adv., 2014, 4, 48741
DOI: 10.1039/C4RA09046B

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