PMID- 32325405
OWN - NLM
STAT- MEDLINE
DCOM- 20210310
LR  - 20210310
IS  - 1878-1705 (Electronic)
IS  - 1567-5769 (Linking)
VI  - 84
DP  - 2020 Jul
TI  - Physiological concentrations of bilirubin control inflammatory response by 
      inhibiting NF-kappaB and inflammasome activation.
PG  - 106520
LID - S1567-5769(20)30389-1 [pii]
LID - 10.1016/j.intimp.2020.106520 [doi]
AB  - Bilirubin, as the final product of heme metabolism, has both toxic and beneficial 
      effects on humans depending on its serum concentration. So far, whether and how 
      physiological concentrations of bilirubin influence inflammation is largely 
      unknown. In the current study, we established inflammatory cell models of murine 
      peritoneal macrophages (PMs) and bone marrow-derived macrophages (BMDMs) by 
      stimulating the cells with either lipopolysaccharide (LPS) alone or with various 
      inflammasome stimuli. In addition, a model of mouse sepsis induced by 
      intraperitoneal injection of LPS was also employed. We found that bilirubin, 
      although used at physiological concentrations, could control inflammation both in 
      vitro and in vivo. In vitro, bilirubin inhibited caspase-1 maturation and IL-1beta 
      secretion in NLRP3, AIM2, and NLRC4 inflammasomes. Besides, bilirubin inhibited 
      the secretion of TNF-alpha and IL-6 in LPS-primed macrophages by reduced 
      phosphorylation of IkappaB-alpha and p65, indicating the inhibition of the NF-kappaB pathway. 
      In vivo, bilirubin significantly inhibited the release of IL-1beta and TNF-alpha, 
      resulting in an increased survival rate of mice with LPS-induced sepsis. Our 
      study demonstrates a protective role of physiological concentrations of bilirubin 
      against inflammation, the mechanisms of which involve the inhibition of the NF-kappaB 
      signaling pathway as well as control of the activation of inflammasomes. 
      Bilirubin could therefore be considered an endogenous regulatory molecule 
      modulating inflammation. In defined doses, bilirubin could be applied as a 
      potential medication against inflammation and inflammasome-related diseases.
CI  - Copyright (c) 2020 Elsevier B.V. All rights reserved.
FAU - Li, Yufei
AU  - Li Y
AD  - Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, 
      Zhejiang University, Hangzhou 310058, China.
FAU - Huang, Bo
AU  - Huang B
AD  - School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, 
      China.
FAU - Ye, Tingting
AU  - Ye T
AD  - Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, 
      Zhejiang University, Hangzhou 310058, China.
FAU - Wang, Yi
AU  - Wang Y
AD  - Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, 
      Zhejiang University, Hangzhou 310058, China.
FAU - Xia, Dajing
AU  - Xia D
AD  - School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, 
      China.
FAU - Qian, Jing
AU  - Qian J
AD  - Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, 
      Zhejiang University, Hangzhou 310058, China. Electronic address: 
      jingqian@zju.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20200420
PL  - Netherlands
TA  - Int Immunopharmacol
JT  - International immunopharmacology
JID - 100965259
RN  - 0 (IL1B protein, mouse)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Tnf protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.22.36 (Caspase 1)
RN  - RFM9X3LJ49 (Bilirubin)
SB  - IM
MH  - Animals
MH  - Bilirubin/*immunology
MH  - Caspase 1/immunology
MH  - Inflammasomes/*immunology
MH  - Inflammation/*immunology
MH  - Interleukin-1beta/immunology
MH  - Lipopolysaccharides/immunology
MH  - Macrophages, Peritoneal/immunology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - NF-kappa B/*immunology
MH  - Sepsis/chemically induced/immunology
MH  - Tumor Necrosis Factor-alpha/immunology
OTO - NOTNLM
OT  - Bilirubin
OT  - IL-1beta
OT  - Inflammasome
OT  - NF-kappaB
OT  - NLRP3
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2020/04/24 06:00
MHDA- 2021/03/11 06:00
CRDT- 2020/04/24 06:00
PHST- 2020/02/13 00:00 [received]
PHST- 2020/03/28 00:00 [revised]
PHST- 2020/04/14 00:00 [accepted]
PHST- 2020/04/24 06:00 [pubmed]
PHST- 2021/03/11 06:00 [medline]
PHST- 2020/04/24 06:00 [entrez]
AID - S1567-5769(20)30389-1 [pii]
AID - 10.1016/j.intimp.2020.106520 [doi]
PST - ppublish
SO  - Int Immunopharmacol. 2020 Jul;84:106520. doi: 10.1016/j.intimp.2020.106520. Epub 
      2020 Apr 20.