title: Carbon monoxide decreases interleukin-1β levels in the lung through the induction of pyrin.
abstract: Carbon monoxide (CO) can act as an anti-inflammatory effector in mouse models of lung injury and disease, through the downregulation of pro-inflammatory cytokines production, though the underlying mechanisms remain unclear. The nucleotide-binding oligomerization domain-, leucine-rich region-, and pyrin domain-containing-3 (NLRP3) inflammasome is a protein complex that regulates the maturation and secretion of pro-inflammatory cytokines, including interleukin-1β (IL-1β). In this report, we show that the CO-releasing molecule (CORM-2) can stimulate the expression of pyrin, a negative regulator of the NLRP3 inflammasome. CORM-2 increased the transcription of pyrin in the human leukemic cell line (THP-1) in the absence and presence of lipopolysaccharide (LPS). In THP-1 cells, CORM-2 treatment dose-dependently reduced the activation of caspase-1 and the secretion of IL-1β, and increased the levels of IL-10, in response to LPS and adenosine 5'-triphosphate (ATP), an NLRP3 inflammasome activation model. Genetic interference of IL-10 by small interfering RNA (siRNA) reduced the effectiveness of CORM-2 in inhibiting IL-1β production and in inducing pyrin expression. Genetic interference of pyrin by siRNA increased IL-1β production in response to LPS and ATP, and reversed CORM-2-dependent inhibition of caspase-1 activation. CO inhalation (250 ppm) in vivo increased the expression of pyrin and IL-10 in lung and spleen, and decreased the levels of IL-1β induced by LPS. Consistent with the induction of pyrin and IL-10, and the downregulation of lung IL-1β production, CO provided protection in a model of acute lung injury induced by intranasal LPS administration. These results provide a novel mechanism underlying the anti-inflammatory effects of CO, involving the IL-10-dependent upregulation of pyrin expression.
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Seul-Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Anatomy, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Jinhyun
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Department of Pathology, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Jeong-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Anatomy, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Gyeong Jae
authors.initials: GJ
authors.lastname: Cho
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical Center, New York, NY, USA.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
authors.forename: Hun Taeg
authors.initials: HT
authors.lastname: Chung
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000071198:Pyrin / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071198:Pyrin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016753:Interleukin-10; D002248:Carbon Monoxide