PMID- 31156650
OWN - NLM
STAT- MEDLINE
DCOM- 20200909
LR  - 20200909
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 10
DP  - 2019
TI  - Chemotherapeutic Agent Paclitaxel Mediates Priming of NLRP3 Inflammasome 
      Activation.
PG  - 1108
LID - 10.3389/fimmu.2019.01108 [doi]
LID - 1108
AB  - Paclitaxel is a chemotherapeutic drug commonly used to treat different types of 
      cancer. In addition to its antitumor effect, paclitaxel is also known to promote 
      Toll-like receptor (TLR) 4-dependent inflammatory responses, which may lower its 
      chemotherapeutic efficacy. However, it remains unclear whether paclitaxel is able 
      to affect inflammasome signaling in myeloid or cancer cells. Therefore, we 
      examined the potential effect of paclitaxel on the activation of an inflammasome 
      complex by examining caspase-1 activation and interleukin (IL)-1beta secretion in 
      bone marrow-derived macrophages (BMDMs). The results showed that treatment with 
      paclitaxel alone or following LPS priming failed to trigger the secretion of 
      active caspase-1 and IL-1beta from BMDMs. However, paclitaxel could induce robust 
      activation of caspase-1 in BMDMs in the presence of NLRP3 inflammasome-activating 
      signal 2, such as ATP or nigericin. This paclitaxel/ATP-mediated inflammasome 
      activation was completely abrogated in Nlrp3-deficient macrophages. 
      Mechanistically, paclitaxel treatment induced robust activation of the TLR4 
      signaling cascade, including phosphorylation of IkappaB and JNK and upregulation of 
      proinflammatory cytokine mRNA levels in a TLR4-dependent manner. In contrast, 
      paclitaxel treatment alone did not induce mitochondrial damages such as the loss 
      of the mitochondrial membrane potential and production of mitochondrial ROS. 
      These findings suggest that paclitaxel can drive the priming of signal-mediated 
      events for NLRP3 activation but not a second signal-triggered phenomenon such as 
      mitochondrial damage. This suggestion was supported by the observations that 
      paclitaxel treatment caused robust IL-1beta production in macrophages in the 
      presence of cell-free medium derived from growth of injured cells and also in the 
      spleen of mice. Collectively, our data strongly indicate that paclitaxel is able 
      to facilitate the activation of NLRP3 inflammasome signaling in a certain 
      physiological environment.
FAU - Son, Seunghwan
AU  - Son S
AD  - Department of Microbiology and Immunology, Institute for Immunology and 
      Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei 
      University College of Medicine, Seoul, South Korea.
FAU - Shim, Do-Wan
AU  - Shim DW
AD  - Department of Microbiology and Immunology, Institute for Immunology and 
      Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei 
      University College of Medicine, Seoul, South Korea.
FAU - Hwang, Inhwa
AU  - Hwang I
AD  - Department of Microbiology and Immunology, Institute for Immunology and 
      Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei 
      University College of Medicine, Seoul, South Korea.
FAU - Park, Jong-Hwan
AU  - Park JH
AD  - BK 21 PLUS Project Team, Laboratory Animal Medicine, College of Veterinary 
      Medicine, Chonnam National University, Gwangju, South Korea.
FAU - Yu, Je-Wook
AU  - Yu JW
AD  - Department of Microbiology and Immunology, Institute for Immunology and 
      Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei 
      University College of Medicine, Seoul, South Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190516
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (IL1B protein, human)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Reactive Oxygen Species)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 3.4.22.36 (Caspase 1)
RN  - P88XT4IS4D (Paclitaxel)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Antineoplastic Agents, Phytogenic/*pharmacology
MH  - Caspase 1/metabolism
MH  - Inflammasomes/*immunology/*metabolism
MH  - Interleukin-1beta/biosynthesis
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Macrophages/drug effects/immunology/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/*metabolism
MH  - Paclitaxel/*pharmacology
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/drug effects
PMC - PMC6532018
OTO - NOTNLM
OT  - NLRP3
OT  - Toll-like receptor 4
OT  - caspase-1
OT  - chemotherapy
OT  - inflammasome
OT  - interleukin-1beta
OT  - paclitaxel
EDAT- 2019/06/04 06:00
MHDA- 2020/09/10 06:00
PMCR- 2019/01/01
CRDT- 2019/06/04 06:00
PHST- 2019/02/14 00:00 [received]
PHST- 2019/05/01 00:00 [accepted]
PHST- 2019/06/04 06:00 [entrez]
PHST- 2019/06/04 06:00 [pubmed]
PHST- 2020/09/10 06:00 [medline]
PHST- 2019/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2019.01108 [doi]
PST - epublish
SO  - Front Immunol. 2019 May 16;10:1108. doi: 10.3389/fimmu.2019.01108. eCollection 
      2019.