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: Seul-Ki Kim, Yeonsoo Joe, Yingqing Chen, Jinhyun Ryu, Jeong-Hee Lee, Gyeong Jae Cho, Stefan W Ryter, Hun Taeg Chung
• Journal: Cellular & molecular immunology (Cell Mol Immunol) Vol. 14 Issue 4 Pg. 349-359 (Apr 2017) ISSN: 2042-0226 [Electronic] China
• PMID: 26435068 (Publication Type: Journal Article)

Chemical References

• Interleukin-1beta
• Lipopolysaccharides
• Pyrin
• RNA, Messenger
• RNA, Small Interfering
• Interleukin-10
• Carbon Monoxide

Topics

• Animals
• Carbon Monoxide (pharmacology)
• Cell Line
• Down-Regulation (drug effects)
• Humans
• Interleukin-10 (metabolism)
• Interleukin-1beta (metabolism)
• Lipopolysaccharides (pharmacology)
• Lung (drug effects, metabolism)
• Mice, Inbred C57BL
• Models, Biological
• Pyrin (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (metabolism)