PMID- 30805671
OWN - NLM
STAT- MEDLINE
DCOM- 20200702
LR  - 20200702
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Linking)
VI  - 93
IP  - 5
DP  - 2019 May
TI  - Inhibition of thymocyte autophagy-associated CD4(+)T thymopoiesis is involved in 
      asthma susceptibility in mice exposed to caffeine prenatally.
PG  - 1323-1335
LID - 10.1007/s00204-019-02418-5 [doi]
AB  - Our previous studies demonstrated that prenatal caffeine exposure (PCE) caused 
      thymopoiesis inhibition, immune disorders, and airway remodeling in offspring, 
      which raises the question of whether PCE is a risk factor for postnatal asthma. 
      Meanwhile, the mechanism of PCE-induced thymopoiesis inhibition is not clear yet. 
      Considering caffeine's pro-autophagy effects (lacking evidence in thymus) and the 
      important role of autophagy in maintaining thymopoiesis, this study aimed to 
      investigate whether PCE contributes to asthma susceptibility, and further explore 
      the molecular mechanisms of thymopoiesis inhibition from the perspective of 
      pro-autophagy effects of caffeine both in vivo and in vitro. The PCE mouse model 
      was established by 96 mg/kg/day caffeine administration from gestational day (GD) 
      9-GD 18, and an asthma model was established on the offspring by ovalbumin 
      sensitization and challenge. The results confirmed our hypothesis that PCE could 
      suppress pulmonary CD4(+)T development and aggravate allergen-induced asthma 
      symptoms in the offspring. In fetuses, PCE significantly suppressed A2AR-PKA 
      signaling, upregulated Beclin1-LC3II autophagy, promoted Bcl10 degradation, 
      reduced A20 expression, and inhibited CD4(+)T thymopoiesis. Similar results were 
      also observed in 4 microM caffeine-treated thymocytes in vitro. Moreover, inhibiting 
      A2AR by antagonist (SCH 58261) performed the same downstream biological effects 
      as caffeine treatment, and autophagy inhibitor (BafilomycinA1) clearly abolished 
      the caffeine-induced Bcl10 degradation and A20 suppression. In conclusion, our 
      findings, for the first time, showed that PCE could attenuate CD4(+)T 
      thymopoiesis and suppress pulmonary CD4(+)T development by directly enhancing 
      autophagy in thymocytes, and provided a firm experimental evidence that PCE is a 
      risk factor for postnatal asthma.
FAU - Liu, Han-Xiao
AU  - Liu HX
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      185, East Lake Road, Wuhan, 430071, China.
FAU - Yan, Hui-Yi
AU  - Yan HY
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      185, East Lake Road, Wuhan, 430071, China.
AD  - Wuhan Mental Health Center, Wuhan Hospital for Psychotherapy, Wuhan, 430012, 
      China.
FAU - Qu, Wen
AU  - Qu W
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      185, East Lake Road, Wuhan, 430071, China.
FAU - Wen, Xiao
AU  - Wen X
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      185, East Lake Road, Wuhan, 430071, China.
FAU - Hou, Li-Fang
AU  - Hou LF
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      185, East Lake Road, Wuhan, 430071, China.
FAU - Zhao, Wen-Hao
AU  - Zhao WH
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      185, East Lake Road, Wuhan, 430071, China.
FAU - Ping, Jie
AU  - Ping J
AUID- ORCID: 0000-0002-9168-1811
AD  - Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 
      185, East Lake Road, Wuhan, 430071, China. pingjie@whu.edu.cn.
LA  - eng
GR  - 81872663/National Natural Science Foundation of China/International
GR  - 81673215/National Natural Science Foundation of China/International
GR  - 2017060201010199/Applied Fundamental Research Project of Wuhan/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190225
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 0 (Central Nervous System Stimulants)
RN  - 3G6A5W338E (Caffeine)
SB  - IM
MH  - Animals
MH  - Asthma/*etiology
MH  - Autophagy/drug effects
MH  - CD4-Positive T-Lymphocytes/metabolism
MH  - Caffeine/administration & dosage/*toxicity
MH  - Central Nervous System Stimulants/administration & dosage/toxicity
MH  - Female
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Pregnancy
MH  - Prenatal Exposure Delayed Effects/*physiopathology
MH  - Thymocytes/cytology/*drug effects
OTO - NOTNLM
OT  - Asthma
OT  - Autophagy
OT  - CD4+T deviation
OT  - Immunotoxicity
OT  - Prenatal caffeine exposure
OT  - Thymocyte
EDAT- 2019/02/26 06:00
MHDA- 2020/07/03 06:00
CRDT- 2019/02/27 06:00
PHST- 2018/10/21 00:00 [received]
PHST- 2019/02/21 00:00 [accepted]
PHST- 2019/02/26 06:00 [pubmed]
PHST- 2020/07/03 06:00 [medline]
PHST- 2019/02/27 06:00 [entrez]
AID - 10.1007/s00204-019-02418-5 [pii]
AID - 10.1007/s00204-019-02418-5 [doi]
PST - ppublish
SO  - Arch Toxicol. 2019 May;93(5):1323-1335. doi: 10.1007/s00204-019-02418-5. Epub 
      2019 Feb 25.