Glibenclamide inhibits NLRP3 inflammasome-mediated IL-1β secretion in human trophoblasts.

Abstract

Infection-associated pregnancy complications cause premature delivery. Caspase-1 is involved in the maturation of interleukin (IL)-1β, which is activated by the NLRP3 inflammasome. To characterize the significance of the NLRP3 inflammasome pathway in the placenta, the effects of activators and inhibitors on NLRP3-related molecules were examined using isolated primary trophoblasts. Caspase-1 and IL-1β mRNA expression was markedly increased in response to lipopolysaccharide (LPS), a toll-like receptor (TLR)4 ligand. Treatment with the potassium ionophore nigericin significantly increased the level of activated caspase-1. Treatment with either LPS or nigericin stimulated IL-1β secretion, whereas pretreatment with the ATP-sensitive K+ channel inhibitor glibenclamide, the Rho-associated coiled-coil kinase inhibitor Y-27632, or a caspase-1 inhibitor significantly decreased nigericin-induced IL-1β secretion. In addition, dibutyryl-cAMP, which induces trophoblast differentiation, decreased expression of NLRP3, caspase-1, and IL-1β. These findings suggest that trophoblasts can secrete IL-1β through the NLRP3/caspase-1 pathway, which is suppressed by glibenclamide, and that the TLR4-mediated NLRP3 inflammasome pathway is more likely to be stimulated in undifferentiated than differentiated trophoblasts. Our data support the hypothesis that inhibition of the NLRP3 inflammasome can suppress placental inflammation-associated disorders.

• Authors: Kazuhiro Tamura, Gen Ishikawa, Mikihiro Yoshie, Wakana Ohneda, Akihito Nakai, Toshiyuki Takeshita, Eiichi Tachikawa
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 135 Issue 2 Pg. 89-95 (Oct 2017) ISSN: 1347-8648 [Electronic] Japan
• PMID: 29056256 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Chemical References

• Amides
• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Potassium Channel Blockers
• Potassium Ionophores
• Pyridines
• Y 27632
• Bucladesine
• Caspase 1
• Glyburide

Topics

• Amides (pharmacology)
• Bucladesine (pharmacology)
• Caspase 1 (metabolism, physiology)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Female
• Glyburide (pharmacology)
• Humans
• Inflammasomes (physiology)
• Interleukin-1beta (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism, physiology)
• Potassium Channel Blockers (pharmacology)
• Potassium Ionophores (pharmacology)
• Pregnancy
• Pyridines (pharmacology)
• Trophoblasts (cytology, metabolism)
• U937 Cells