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Human soluble thrombomodulin-induced blockade of peripheral HMGB1-dependent allodynia in mice requires both the lectin-like and EGF-like domains.

Authors
  • Hayashi, Yusuke1
  • Tsujita, Ryuichi2
  • Tsubota, Maho1
  • Saeki, Haruka1
  • Sekiguchi, Fumiko1
  • Honda, Goichi3
  • Kawabata, Atsufumi4
  • 1 Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. , (Japan)
  • 2 Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan; Project Management Development, Asahi Kasei Pharma Corporation, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan. , (Japan)
  • 3 Medical Affairs Development, Asahi Kasei Pharma Corporation, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan. , (Japan)
  • 4 Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. Electronic address: [email protected] , (Japan)
Type
Published Article
Journal
Biochemical and Biophysical Research Communications
Publisher
Elsevier
Publication Date
Nov 13, 2017
Identifiers
DOI: 10.1016/j.bbrc.2017.11.079
PMID: 29146186
Source
Medline
Keywords
License
Unknown

Abstract

Thrombomodulin (TM), an endothelial protein with anti-coagulant activity, is composed of 5 domains, D1-D5. Recombinant human soluble TM (TMα) consisting of D1-D3, which is generated in CHO cells, suppresses inflammatory and nociceptive signals by inactivating high mobility group box 1 (HMGB1), one of damage-associated molecular patterns. TMα sequesters HMGB1 with the lectin-like D1 and promotes its degradation by thrombin binding to the EGF-like D2. We prepared TM's D123, D1 and D2 by the protein expression system of yeast, and evaluated their effects on HMGB1 degradation in vitro and on the allodynia caused by HMGB1 in distinct redox forms in mice in vivo. TMα and TM's D123, but not D1, promoted the thrombin-dependent degradation of all-thiol (at-HMGB1) and disulfide HMGB1 (ds-HMGB1), an effect mimicked by TM's D2, though to a lesser extent. Intraplantar administration of TMα and TM's D123, but not D1, D2 or D1 plus D2, strongly prevented the mechanical allodynia caused by intraplantar at-HMGB1, ds-HMGB1 or lipopolysaccharide in mice. Our data suggest that, apart from the role of D3, TMα and TM's D123 require both lectin-like D1 capable of sequestering HMGB1 and EGF-like D2 responsible for thrombin-dependent degradation of HMGB1, in abolishing the allodynia caused by exogenous or endogenous HMGB1.

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