title: Efficacy of DHMEQ, a NF-κB inhibitor, in islet transplantation: I. HMGB1 suppression by DHMEQ prevents early islet graft damage.
abstract: BACKGROUND
  Pancreatic islet transplantation (PITx) is an attractive treatment option for restoring appropriate glucose homeostasis in type 1 diabetes patients. Although islet grafts can successfully engraft after PITx, large numbers of islet grafts are required mainly because immune reactions, including inflammation, destroy islet grafts. In these processes, nuclear factor (NF)-κB plays a central role. We hypothesized that the inhibition of NF-κB activation would ameliorate inflammatory responses after PITx and aid successful engraftment.
  
  
  METHODS
  To test this hypothesis, a newly developed NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), was used on a syngeneic mouse PITx model. One hundred seventy-five islets from C57BL/6 (B6) mice were transplanted into streptozotocin-induced diabetic B6 mice. The recipient mice were administered DHMEQ for 1, 2, or 3 days after PITx. The underlying mechanisms of DHMEQ on islet graft protection were investigated in an in vitro coculture model of pancreatic islets and macrophages.
  
  
  RESULTS
  With a vehicle treatment, only 11.1% of the islet-recipients achieved normoglycemia after PITx. In sharp contrast, DHMEQ treatment markedly improved the normoglycemic rate, which was associated with the suppression of serum high mobility group complex-1 (HMGB1) and proinflammatory cytokines, including tumor necrosis factor-α, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, interleukin-1β, and interleukin-6, after PITx. In a murine macrophage-like cell line, DHMEQ inhibited HMGB1-driven activation and proinflammatory cytokine secretion and further prevented death isolated islets after coculture with these activated macrophages.
  
  
  CONCLUSIONS
  Inhibition of NF-κB activation by DHMEQ after PITx reduces the HMGB1-triggered proinflammatory responses and results in engraftment of transplanted islets even with fewer islet grafts.
authors.affiliation: First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kuraya
authors.forename: Masaaki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Koshizuka
authors.forename: Masaomi
authors.initials: M
authors.lastname: Ogura
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Yoh
authors.initials: Y
authors.lastname: Asahi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kamachi
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Michiaki
authors.initials: M
authors.lastname: Matsushita
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003512:Cyclohexanones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D024243:HMGB1 Protein / Q000097:blood*; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects*; D008081:Liposomes; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011183:Postoperative Complications / Q000517:prevention & control*; D013311:Streptozocin
chemical_list: D001549:Benzamides; D003512:Cyclohexanones; D024243:HMGB1 Protein; D008081:Liposomes; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin; D013311:Streptozocin