Toll-like receptor 4 antagonist TAK-242 inhibits autoinflammatory symptoms in DITRA

Akitaka Shibata, Kazumitsu Sugiura, Yasuhide Furuta, Yoshiko Mukumoto, Osamu Kaminuma, Masashi Akiyama

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), and loss-of-function mutations in IL36RN define a recessively inherited autoinflammatory disease named “deficiency of IL-36Ra” (DITRA). DITRA causes systemic autoinflammatory diseases, including generalized pustular psoriasis (GPP), an occasionally life-threatening disease that is characterized by widespread sterile pustules on the skin, fever and other systemic symptoms. GPP can present at any age, and provocative factors include various infections, medicines and pregnancy. Objective We aimed to elucidate the role of toll-like receptor 4 (TLR4) signaling in DITRA and to innovate an efficient treatment for DITRA. Methods We generated Il36rn−/− mice and treated them with TLR4 agonist to establish DITRA model mice. Furthermore, we administrated TLR4 antagonist TAK-242 to the model mice to inhibit the DITRA symptoms. Result Il36rn−/− mice treated by TLR4 agonist showed autoinflammatory symptoms in skin, articulation and liver. Thus, we established model mice for DITRA or GPP that show cutaneous, articular, and hepatic autoinflammatory symptoms typical of DITRA or GPP: sterile pustules on the skin, liver abscesses and enthesitis of the hind paws. Additionally, these symptoms were canceled by TAK-242 administration. We demonstrated the inhibitory effects of the TLR4 antagonist TAK-242 on the autoinflammatory symptoms exhibited by the DITRA models. Conclusion We suggested that blockage of TLR4 signaling is a promising treatment for DITRA and GPP.

Original languageEnglish
Pages (from-to)28-38
Number of pages11
JournalJournal of Autoimmunity
Volume80
DOIs
Publication statusPublished - 01-06-2017

Fingerprint

Toll-Like Receptor 4
Psoriasis
Skin
Deficiency Diseases
Liver Abscess
Age Factors
Liver
Fever
Joints
ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
Pregnancy
Mutation
Infection

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Shibata, Akitaka ; Sugiura, Kazumitsu ; Furuta, Yasuhide ; Mukumoto, Yoshiko ; Kaminuma, Osamu ; Akiyama, Masashi. / Toll-like receptor 4 antagonist TAK-242 inhibits autoinflammatory symptoms in DITRA. In: Journal of Autoimmunity. 2017 ; Vol. 80. pp. 28-38.
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abstract = "Background IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), and loss-of-function mutations in IL36RN define a recessively inherited autoinflammatory disease named “deficiency of IL-36Ra” (DITRA). DITRA causes systemic autoinflammatory diseases, including generalized pustular psoriasis (GPP), an occasionally life-threatening disease that is characterized by widespread sterile pustules on the skin, fever and other systemic symptoms. GPP can present at any age, and provocative factors include various infections, medicines and pregnancy. Objective We aimed to elucidate the role of toll-like receptor 4 (TLR4) signaling in DITRA and to innovate an efficient treatment for DITRA. Methods We generated Il36rn−/− mice and treated them with TLR4 agonist to establish DITRA model mice. Furthermore, we administrated TLR4 antagonist TAK-242 to the model mice to inhibit the DITRA symptoms. Result Il36rn−/− mice treated by TLR4 agonist showed autoinflammatory symptoms in skin, articulation and liver. Thus, we established model mice for DITRA or GPP that show cutaneous, articular, and hepatic autoinflammatory symptoms typical of DITRA or GPP: sterile pustules on the skin, liver abscesses and enthesitis of the hind paws. Additionally, these symptoms were canceled by TAK-242 administration. We demonstrated the inhibitory effects of the TLR4 antagonist TAK-242 on the autoinflammatory symptoms exhibited by the DITRA models. Conclusion We suggested that blockage of TLR4 signaling is a promising treatment for DITRA and GPP.",
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Toll-like receptor 4 antagonist TAK-242 inhibits autoinflammatory symptoms in DITRA. / Shibata, Akitaka; Sugiura, Kazumitsu; Furuta, Yasuhide; Mukumoto, Yoshiko; Kaminuma, Osamu; Akiyama, Masashi.

In: Journal of Autoimmunity, Vol. 80, 01.06.2017, p. 28-38.

Research output: Contribution to journalArticle

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AU - Sugiura, Kazumitsu

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N2 - Background IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), and loss-of-function mutations in IL36RN define a recessively inherited autoinflammatory disease named “deficiency of IL-36Ra” (DITRA). DITRA causes systemic autoinflammatory diseases, including generalized pustular psoriasis (GPP), an occasionally life-threatening disease that is characterized by widespread sterile pustules on the skin, fever and other systemic symptoms. GPP can present at any age, and provocative factors include various infections, medicines and pregnancy. Objective We aimed to elucidate the role of toll-like receptor 4 (TLR4) signaling in DITRA and to innovate an efficient treatment for DITRA. Methods We generated Il36rn−/− mice and treated them with TLR4 agonist to establish DITRA model mice. Furthermore, we administrated TLR4 antagonist TAK-242 to the model mice to inhibit the DITRA symptoms. Result Il36rn−/− mice treated by TLR4 agonist showed autoinflammatory symptoms in skin, articulation and liver. Thus, we established model mice for DITRA or GPP that show cutaneous, articular, and hepatic autoinflammatory symptoms typical of DITRA or GPP: sterile pustules on the skin, liver abscesses and enthesitis of the hind paws. Additionally, these symptoms were canceled by TAK-242 administration. We demonstrated the inhibitory effects of the TLR4 antagonist TAK-242 on the autoinflammatory symptoms exhibited by the DITRA models. Conclusion We suggested that blockage of TLR4 signaling is a promising treatment for DITRA and GPP.

AB - Background IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), and loss-of-function mutations in IL36RN define a recessively inherited autoinflammatory disease named “deficiency of IL-36Ra” (DITRA). DITRA causes systemic autoinflammatory diseases, including generalized pustular psoriasis (GPP), an occasionally life-threatening disease that is characterized by widespread sterile pustules on the skin, fever and other systemic symptoms. GPP can present at any age, and provocative factors include various infections, medicines and pregnancy. Objective We aimed to elucidate the role of toll-like receptor 4 (TLR4) signaling in DITRA and to innovate an efficient treatment for DITRA. Methods We generated Il36rn−/− mice and treated them with TLR4 agonist to establish DITRA model mice. Furthermore, we administrated TLR4 antagonist TAK-242 to the model mice to inhibit the DITRA symptoms. Result Il36rn−/− mice treated by TLR4 agonist showed autoinflammatory symptoms in skin, articulation and liver. Thus, we established model mice for DITRA or GPP that show cutaneous, articular, and hepatic autoinflammatory symptoms typical of DITRA or GPP: sterile pustules on the skin, liver abscesses and enthesitis of the hind paws. Additionally, these symptoms were canceled by TAK-242 administration. We demonstrated the inhibitory effects of the TLR4 antagonist TAK-242 on the autoinflammatory symptoms exhibited by the DITRA models. Conclusion We suggested that blockage of TLR4 signaling is a promising treatment for DITRA and GPP.

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