Lipopolysaccharide/adenosine triphosphate-mediated signal transduction in the regulation of NLRP3 protein expression and
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Inflammation Research
ORIGINAL RESEARCH PAPER
Lipopolysaccharide/adenosine triphosphate-mediated signal transduction in the regulation of NLRP3 protein expression and caspase-1-mediated interleukin-1b secretion Pei-Chun Liao • Louis Kuoping Chao • Ju-Ching Chou • Wei-Chih Dong • Chien-Nan Lin • Chai-Yi Lin • Ann Chen Shuk-Man Ka • Chen-Lung Ho • Kuo-Feng Hua
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Received: 1 June 2012 / Revised: 31 July 2012 / Accepted: 3 September 2012 / Published online: 18 September 2012 Ó Springer Basel AG 2012
Abstract Objective Reactive oxygen species (ROS) plays a critical role in the regulation of NLRP3 inflammasome activation. However, the ROS-mediated signaling pathways controlling NLRP3 inflammasome activation are not well defined. Methods Using lipopolysaccharide (LPS) and adenosine triphosphate (ATP) activated murine macrophages as the testing model, cytokine release and protein expression were quantified by enzyme-linked immunosorbent assay and Western blot, respectively. ROS was scavenged by N-acetyl cysteine; NADPH oxidase, the major source of ROS, was inhibited by diphenyliodonium, apocynin or
gp91-phox siRNA transfection; and protein kinase was inhibited by its specific inhibitor. Results LPS-induced NLRP3 protein expression was regulated through the NADPH oxidase/ROS/NF-jBdependent, JAK2/PI3-kinase/AKT/NF-jB-dependent, and MAPK-dependent pathways, while ATP-induced caspase-1 activation was regulated through the NADPH oxidase/ ROS-dependent pathway. Conclusions These results demonstrate that ROS regulates not only the priming stage, but also the activation stage, of NLRP3 inflammasome activation in LPS ? ATPactivated macrophages. Keywords NLRP3 inflammasome LPS Reactive oxygen species
Responsible Editor: Graham Wallace. P.-C. Liao J.-C. Chou W.-C. Dong C.-N. Lin C.-Y. Lin K.-F. Hua (&) Department of Biotechnology and Animal Science, National Ilan University, 1, Sec. 1, Shen-Lung Road, Ilan 260, Taiwan e-mail: [email protected] Present Address: P.-C. Liao L. K. Chao Department of Cosmeceutics, China Medical University, Taichung, Taiwan C.-L. Ho Division of Wood Cellulose, Taiwan Forestry Research Institute, Taipei, Taiwan A. Chen Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan S.-M. Ka Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
Introduction Interleukin (IL)-1b is one of the important cytokines rapidly synthesized in an inactive immature form (precursor of IL-1b, proIL-1b) via transcriptional activation in lipopolysaccharide (LPS)-activated macrophages [1]. Unlike that of other cytokines, secretion of mature IL-1b requires processing of its precursor form (proIL-1b) by caspase-1, a cysteine protease [2]. IL-1b can induce inflammatory responses, upregulate host defenses, and function as an immunoadjuvant, causing induction of cyclooxygenase-2, increased expression of adhesion molecules, or synthesis of nitric oxide [3, 4]. IL-1b release is controlled by caspase-1-containing multi-protei
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