A cell-penetrating peptide blocks Toll-like receptor-mediated downstream signaling and ameliorates autoimmune and inflammatory diseases in mice
권혁권, Patra Mahesh Chandra, 신현준, Gui Xiangai, Achek Asma, Panneerselvam Suresh, 김동진, Song Suk-Jong, 홍리원, 김경수, 김양균, Lee Francis Y., 함대현, 이상호, 최상던,
소속 상세정보
권혁권 ( Kwon Hyuk-Kwon )
Ajou University Department of Molecular Science and Technology
( Patra Mahesh Chandra )
Ajou University Department of Molecular Science and Technology
신현준 ( Shin Hyeon-Jun )
Ajou University Department of Molecular Science and Technology
( Gui Xiangai )
Ajou University Department of Molecular Science and Technology
( Achek Asma )
Ajou University Department of Molecular Science and Technology
( Panneerselvam Suresh )
Ajou University Department of Molecular Science and Technology
김동진 ( Kim Dong-Jin )
Kyung Hee University Hospital at Gangdong Department of Internal Medicine
( Song Suk-Jong )
Kyung Hee University Hospital at Gangdong Department of Internal Medicine
홍리원 ( Hong Ri-Won )
Kyung Hee University College of Korean Medicine Department of Science in Korean Medicine
김경수 ( Kim Kyoung-Soo )
Kyung Hee University Hospital at Gangdong East-West Bone and Joint Research Institute
김양균 ( Kim Yang-Gyun )
Kyung Hee University Hospital at Gangdong Department of Internal Medicine
( Lee Francis Y. )
Yale School of Medicine Department of Orthopaedics and Rehabilitation
함대현 ( Hahm Dae-Hyun )
Kyung Hee University School of Medicine Department of Physiology
이상호 ( Lee Sang-Ho )
Kyung Hee University Hospital at Gangdong Department of Internal Medicine
최상던 ( Choi Sang-Dun )
Ajou University Department of Molecular Science and Technology
Abstract
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.
키워드
Drug development; Toll-like receptors
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