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Brazilin selectively disrupts proximal IL-1 receptor signaling complex formation by targeting an IKK-upstream signaling components.
Jeon, Juhee; Lee, Ji Hoon; Park, Kyeong Ah; Byun, Hee Sun; Lee, Hyunji; Lee, Yoonjung; Zhang, Tiejun; Kang, Kidong; Seok, Jeong Ho; Kwon, Hyun-Jung; Han, Man-Deuk; Kang, Seong Wook; Hong, Jang Hee; Hur, Gang Min.
Afiliação
  • Jeon J; Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
  • Lee JH; Department of Physics, Amherst College, Amherst, MA 01002-5000, USA.
  • Park KA; Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
  • Byun HS; Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
  • Lee H; Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
  • Lee Y; Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
  • Zhang T; Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
  • Kang K; Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
  • Seok JH; Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
  • Kwon HJ; Department of Biology, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea.
  • Han MD; Department of Biology, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea.
  • Kang SW; Division of Rheumatology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
  • Hong JH; Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea.
  • Hur GM; Department of Pharmacology, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-747, Republic of Korea. Electronic address: gmhur@cnu.ac.kr.
Biochem Pharmacol ; 89(4): 515-25, 2014 Jun 15.
Article em En | MEDLINE | ID: mdl-24735611
The ligation of interleukin-1 receptor (IL-1R) or tumor necrosis factor receptor 1 (TNFR1) induces the recruitment of adaptor proteins and their concomitant ubiquitination to the proximal receptor signaling complex, respectively. Such are upstream signaling events of IKK that play essential roles in NF-κB activation. Thus, the discovery of a substance that would modulate the recruitment of key proximal signaling elements at the upstream level of IKK has been impending in this field of study. Here, we propose that brazilin, an active compound of Caesalpinia sappan L. (Leguminosae), is a potent NF-κB inhibitor that selectively disrupts the formation of the upstream IL-1R signaling complex. Analysis of upstream signaling events revealed that brazilin markedly abolished the IL-1ß-induced polyubiquitination of IRAK1 and its interaction with IKK-γ counterpart. Notably, pretreatment of brazilin drastically interfered the recruitment of the receptor-proximal signaling components including IRAK1/4 and TRAF6 onto MyD88 in IL-1R-triggerd NF-κB activation. Interestingly, brazilin did not affect the TNF-induced RIP1 ubiquitination and the recruitment of RIP1 and TRAF2 to TNFR1, suggesting that brazilin is effective in selectively suppressing the proximal signaling complex formation of IL-1R, but not that of TNFR1. Moreover, our findings suggest that such a disruption of IL-1R-proximal complex formation by brazilin is not mediated by affecting the heterodimerization of IL-1R and IL-1RAcP. Taken together, the results suggest that the anti-IKK activity of brazilin is induced by targeting IKK upstream signaling components and subsequently disrupting proximal IL-1 receptor signaling complex formation.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia; Benzopiranos/farmacologia; Quinase I-kappa B/antagonistas & inibidores; Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores; Transdução de Sinais/efeitos dos fármacos; Receptor 4 Toll-Like/antagonistas & inibidores; Anti-Inflamatórios não Esteroides/química; Anti-Inflamatórios não Esteroides/isolamento & purificação; Benzopiranos/química; Benzopiranos/isolamento & purificação; Caesalpinia/química; Etnofarmacologia; Genes Reporter/efeitos dos fármacos; Células HEK293; Células HeLa; Humanos; Quinase I-kappa B/metabolismo; Proteínas I-kappa B/antagonistas & inibidores; Proteínas I-kappa B/genética; Proteínas I-kappa B/metabolismo; Quinases Associadas a Receptores de Interleucina-1/genética; Quinases Associadas a Receptores de Interleucina-1/metabolismo; Interleucina-1beta/antagonistas & inibidores; Interleucina-1beta/genética; Interleucina-1beta/metabolismo; Estrutura Molecular; NF-kappa B/agonistas; NF-kappa B/antagonistas & inibidores; NF-kappa B/genética; NF-kappa B/metabolismo; Receptores de Interleucina-1/agonistas; Receptores de Interleucina-1/antagonistas & inibidores; Receptores de Interleucina-1/genética; Receptores de Interleucina-1/metabolismo; Proteínas Recombinantes/química; Proteínas Recombinantes/metabolismo; República da Coreia; Receptor 4 Toll-Like/genética; Receptor 4 Toll-Like/metabolismo; Fator de Necrose Tumoral alfa/antagonistas & inibidores; Fator de Necrose Tumoral alfa/genética; Fator de Necrose Tumoral alfa/metabolismo; Ubiquitinação/efeitos dos fármacos; Madeira/química
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Benzopiranos / Transdução de Sinais / Anti-Inflamatórios não Esteroides / Quinase I-kappa B / Receptor 4 Toll-Like / Quinases Associadas a Receptores de Interleucina-1 País/Região como assunto: America do sul / Asia / Brasil Idioma: En Revista: Biochem Pharmacol Ano de publicação: 2014 Tipo de documento: Article País de publicação: Reino Unido
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Benzopiranos / Transdução de Sinais / Anti-Inflamatórios não Esteroides / Quinase I-kappa B / Receptor 4 Toll-Like / Quinases Associadas a Receptores de Interleucina-1 País/Região como assunto: America do sul / Asia / Brasil Idioma: En Revista: Biochem Pharmacol Ano de publicação: 2014 Tipo de documento: Article País de publicação: Reino Unido