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

in Reproduction
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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. IRF5 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 PTGS2, PGF and PTGFR 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.

 

    Society for Reproduction and Fertility

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    Expression of IRF5 in human myometrium. (A, B and C) Human myometrium was obtained at term Caesarean section from women at term in the absence of labour (term no labour, n = 8 patients) or during labour at term (term in labour, n = 8 patients). (A) Immunohistochemical expression of IRF5. These sections are representative of one patient sample per group. Negative control is also displayed. Original magnification ×100. Scale bar 100 µm. (B) IRF5 mRNA abundance was analysed by qRT-PCR. Data are displayed as box-and-whisker plots (median, interquartile range). *P ≤ 0.05, Mann–Whitney U test. (C) IRF5 protein expression was analysed by Western blotting. Representative Western blot from four patients per group is shown. Data are displayed as box-and-whisker plots (median, interquartile range). *P ≤ 0.05, Mann–Whitney U test. (D) Mice were injected with a single i.p. injection of 15 μg of LPS at 15.5 dpc. Mice were considered in labour on birth of one pup. LPS-treated mice were killed on the birth of one pup, and time-matched vehicle-injected mice were killed directly afterward (n = 4 mice/group). IRF5 mRNA expression in myometrium was analysed by qRT-PCR and the fold change was calculated relative to vehicle group. All data are displayed as mean ± s.e.m. *P < 0.05, unpaired Students t-test. (E) Human myometrial cells were incubated in the absence or presence of 1 ng/mL IL1B or 10 ng/mL TNF for 20 h (n = 6 patients per treatment). IRF5 mRNA expression was analysed by qRT-PCR and the fold change was calculated relative to basal. Data are displayed as mean ± s.e.m. *P ≤ 0.05, paired Students t-test.

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    Effect of siIRF5 on pro-inflammatory cytokines in primary myometrial cells. Human primary myometrial cells were transfected with 50 nM siCONT or 50 nM siIRF5 for 48 h and then treated with (A, B and C) 1 ng/mL IL1B, (D, E and F) 10 ng/mL TNF, (H and I) 250 ng/mL fsl-1 or (J, K and L) 1 μg/mL flagellin (flag) for an additional 20 h (n = 5–7 patients). (A, B, D, E, G, H, J and K) IL1A and IL6 mRNA expression was analysed by qRT-PCR. (C, F, I and L) The concentration of IL6 in the incubation medium was assayed by ELISA. For all data, the fold change was calculated relative to IL1B-, TNF-, fsl-1- or flag-treated cells. Individual data points represent 5–7 independent experiments and displayed as mean ± s.e.m. *P ≤ 0.05 (repeated-measures one-way ANOVA).

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    Effect of siIRF5 on chemokines in primary myometrial cells. Human primary myometrial cells were transfected with 50 nM siCONT or 50 nM siIRF5 for 48 h and then treated with (A, B, C and D) 1 ng/mL IL1B, (E, F, G and H) 10 ng/mL TNF, (I, J, K and L) 250 ng/mL fsl-1 or (M, N, O and P) 1 μg/mL flagellin (flag) for an additional 20 h (n = 5–7 patients). (A, C, E, G, I, K, M, O) CXCL8 and CCL2 mRNA expression was analysed by qRT-PCR. (B, D, F, H, J, L, N, P) The concentration of CXCL8 and CCL2 in the incubation medium was assayed by ELISA. For all data, the fold change was calculated relative to IL1B-, TNF-, fsl-1- or flag-treated cells. Individual data points represent 5–7 independent experiments and displayed as mean ± s.e.m. *P ≤ 0.05 (repeated-measures one-way ANOVA).

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    Effect of siIRF5 on cell adhesion molecules in primary myometrial cells. Human primary myometrial cells were transfected with 50 nM siCONT or 50 nM siIRF5 for 48 h and then treated with (A, B, C and D) 1 ng/mL IL1B, (E, F, G and H) 10 ng/mL TNF, (I, J, K and L) 250 ng/mL fsl-1 or (M, N, O and P) 1 μg/mL flagellin (flag) for an additional 20 h (n = 5–7 patients). (A, C, E, G, I, K, M, O) ICAM1 and VCAM1 mRNA expression was analysed by qRT-PCR. (B, D, F, H, J, L, N and P) The concentration of sICAM1 and sVCAM1 in the incubation medium was assayed by ELISA. For all data, the fold change was calculated relative to IL1B-, TNF-, fsl-1- or flag-treated cells. Individual data points represent 5–7 independent experiments and displayed as mean ± s.e.m. *P ≤ 0.05 (repeated measures one-way ANOVA).

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    Effect of siIRF5 on contraction-associated proteins in primary myometrial cells. Human primary myometrial cells were transfected with 50 nM siCONT or 50 nM siIRF5 for 48 h and then treated with 1 ng/mL IL1B for an additional 20 h (n = 6 patients). (A and B) PTGS2 and PTGFR mRNA expression was analysed by qRT-PCR. (C) The concentration of PGF in the incubation medium was assayed by ELISA. For all data, the fold change was calculated relative to IL1B-treated cells. Individual data points represent 6 independent experiments and displayed as mean ± s.e.m. *P ≤ 0.05 (repeated measures one-way ANOVA).

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    Effect of siIRF5 on NF-κB RELA transcriptional activity. Human myometrial cells were transfected with 0.75 ng NF-κB RELA reporter construct. After 6 h, cells were transfected with 50 nM siCONT or 50 nM siIRF5 for 48 h, then treated with (A) 1 ng/mL IL1B, (B) 10 ng/mL TNF, (C) 250 ng/mL fsl-1 or (D) 1 μg/mL flagellin (flag) for an additional 20 h (n = 6 patients). RELA promoter activity (normalised to Renilla) is expressed as a ratio of luciferase activity of IL1B-, TNF-, fsl-1- or flag-stimulated siCONT transfected cells. Individual data points represent 6 independent experiments and displayed as mean ± s.e.m. *P ≤ 0.05 (repeated-measures one-way ANOVA).

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