跳轉至內容
Merck
  • HMGB1 promotes differentiation syndrome by inducing hyperinflammation via MEK/ERK signaling in acute promyelocytic leukemia cells.

HMGB1 promotes differentiation syndrome by inducing hyperinflammation via MEK/ERK signaling in acute promyelocytic leukemia cells.

Oncotarget (2017-04-14)
Lanlan Tang, Wenwen Chai, Fanghua Ye, Yan Yu, Lizhi Cao, Minghua Yang, Min Xie, Liangchun Yang
摘要

Differentiation therapy based on all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) for the treatment of acute promyelocytic leukemia (APL) is complicated by the development of differentiation syndrome (DS), which can be fatal. We examined the role of HMGB1 (high-mobility group box 1) in DS using both in vitro and in vivo models. HMGB1 and the pro-inflammatory cytokines IL-1β and TNF-α were gradually released from NB4 and HL-60 cells treated with ATRA and/or ATO. Similarly, higher serum HMGB1 levels positively correlated with the clinical status of DS patients. Exogenous HMGB1 promoted rapid release of IL-1β and TNF-α as well as elevated expression of ICAM-1, without altering cell differentiation. Exogenous HMGB1 also enhanced pulmonary infiltration and up-regulated ICAM-1 expression in the ATRA-treated DS mouse. Pharmacological inhibition or depletion of MEK1/2 reduced the cytokine levels and suppressed expression of ICAM-1 and the adhesion of HMGB1-treated NB4 cells to endothelial cells, implicating MEK/ERK signaling in the response to HMGB1 during DS. Treatment with a HMGB1-neutralizing antibody reduced secretion of TNF-α and IL-1β, arrested the elevation of ICAM-1 and blunted the activation of ERK1/2 in ATRA-induced NB4 cells. The HMGB1-neutralizing antibody also decreased ICAM-1 expression and reduced mortality in ATRA-treated DS model mice. These findings demonstrate that released HMGB1 is central to DS, and that targeting HMGB1 may be of therapeutic value in the treatment of DS.

材料
產品編號
品牌
產品描述

Sigma-Aldrich
HMG-1 人, lyophilized powder, ≥90% (SDS-PAGE), Histidine-tagged, recombinant, expressed in E. coli
Sigma-Aldrich
Monoclonal Anti-I-CAM-1 (CD54) antibody produced in mouse, clone 8.4A6, purified immunoglobulin
Sigma-Aldrich
Monoclonal Anti-CD11b antibody produced in mouse, clone ICRF44, purified immunoglobulin, buffered aqueous solution