Carbon monoxide decreases interleukin-1β levels in the lung through the induction of pyrin

摘要

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.