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KMID : 0620920190510040050
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Experimental & Molecular Medicine
2019 Volume.51 No. 4 p.50 ~ p.50
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A cell-penetrating peptide blocks Toll-like receptor-mediated downstream signaling and ameliorates autoimmune and inflammatory diseases in mice
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Kwon Hyuk-Kwon
Patra Mahesh Chandra
Shin Hyeon-Jun
Gui Xiangai
Achek Asma
Panneerselvam Suresh
Kim Dong-Jin
Song Suk-Jong
Hong Ri-Won
Kim Kyoung-Soo
Kim Yang-Gyun
Lee Francis Y.
Hahm Dae-Hyun
Lee Sang-Ho
Choi Sang-Dun
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Abstract
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Toll-like receptors (TLRs) recognize pathogen/damage-associated molecular patterns and initiate inflammatory signaling cascades. Occasionally, overexpression of TLRs leads to the onset of numerous inflammatory diseases, necessitating the development of selective inhibitors to allow a protective yet balanced immune response. Here, we demonstrate that a novel peptide (TIP1) derived from Toll/interleukin-1 receptor (TIR) domain-containing adapter protein inhibited multiple TLR signaling pathways (MyD88-dependent and MyD88-independent) in murine and human cell lines. TIP1 also inhibited NLRP3-mediated IL-1β secretion, as we validated at both the protein and mRNA levels. Biophysical experiments confirmed that TIP1 specifically binds to the BB loop of the TLR4-TIR domain. Animal studies revealed that TIP1 inhibited the secretion of lipopolysaccharide (LPS)-induced proinflammatory cytokines in collagen-induced arthritis (CIA) and kaolin/carrageenan-induced arthritis (K/C) rodent models. TIP1 also rescued animals from sepsis and from LPS-induced kidney/liver damage. Importantly, TIP1 ameliorated the symptoms of rheumatoid arthritis in CIA and K/C rodent models, suggesting that TIP1 has therapeutic potential for the treatment of TLR-mediated autoimmune/inflammatory diseases.
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KEYWORD
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Drug development, Toll-like receptors
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