IRF5 is increased in labouring myometrium and regulates pro-labour mediators

Abstract

Preterm birth continues to be the leading cause of neonatal mortality and morbidities that can extend into adult life. Few treatment options stem from our incomplete understanding of the mechanisms of human labour and delivery. Activation of the inflammatory response in gestational tissues by inflammation and/or infection leads to the production of pro-inflammatory and pro-labour mediators, thus preterm birth. Interferon regulatory factor 5 (IRF5) has recently emerged as an important pro-inflammatory transcription factor involved in acute and chronic inflammation. The aims of this study were to determine the expression of IRF5 in human myometrium from labouring and non-labouring women, and whether IRF5 is involved in the genesis of pro-inflammatory and pro-labour mediators induced by pro-inflammatory cytokines or toll-like receptor (TLR) ligands. IRF5 mRNA and protein expression was significantly higher in human myometrium after spontaneous term labour, compared to non-labouring tissues. mRNA expression was also significantly higher in primary myometrial cells treated with the pro-inflammatory cytokines IL1B or TNF. In primary myometrial cells, IRF5 knockdown by siRNA (siIRF5) was associated with significantly decreased expression and or secretion of pro-inflammatory cytokines (IL1A, IL6), chemokines (CXCL8, CCL2), adhesion molecules (ICAM1, VCAM1) and contraction-associated proteins, PGF and when in the presence of IL1B, TNF, fsl-1 (TLR2/6 ligand) or flagellin (TLR5 ligand). siIRF5-transfected cells also displayed decreased NF-κB RELA transcriptional activity in the presence of these preterm birth mediators. Our study suggests a novel role for IRF5 in the regulation of the inflammatory response in human myometrium.

Functional Relationship of Interferon Regulator Factor-5, Interferon-γ, and Hypoxia-Induced Factor-1α with COVID-19 During Pregnancy Outcomes

“…It has also been reported that the suppressed IRF5 production under normoxic conditions modulated (suppressed) the production of other pro-in ammatory cytokines [29]. Furthermow, it has been shown that IRF5 plays a role in the regulation of in ammatory response in myometrium and that the IRF5 expression level increases in the myometrium with labor [13]. Study has shown that gene polymorphisms occurring in IRF5 were associated with recurrent spontaneous abortions [14].…”

“…IRF5, which is a from this IRF family, induces the production of many in ammatory molecules involved in the pathogenesis of autoimmune diseases [11,12]. It has been shown that IRF5 level increases in the myometrium with labor, and gene polymorphisms are associated with recurrent spontaneous abortions [13,14]. It has also been reported that IRF5 plays a role in the "cytokine storm" seen in some infections such as COVID-19 [15].…”