Abstract
The onset of human labour resembles inflammation with increased synthesis of prostaglandins and cytokines. There is evidence from rodent models for an important role for nuclear factor-κB (NF-κB) activity in myometrium which both up-regulates contraction-associated proteins and antagonizes the relaxatory effects of progesterone. Here we show that in the human, although there are no differences in expression of NF-κB p65, or IκB-α between upper- or lower-segment myometrium or before or after labour, there is nuclear localization of serine-256-phospho-p65 and serine-536-phospho-p65 in both upper- and lower-segment myometrium both before and after the onset of labour at term. This shows that NF-κB is active in both upper and lower segment prior to the onset of labour at term. To identify the range of genes regulated by NF-κB we overexpressed p65 in myocytes in culture. This led to NF-κB activation identical to that seen following interleukin (IL)-1β stimulation, including phosphorylation and nuclear translocation of p65 and p50. cDNA microarray analysis showed that NF-κB increased expression of 38 genes principally related to immunity and inflammation. IL-1β stimulation also resulted in an increase in the expression of the same genes. Transfection with siRNA against p65 abolished the response to IL-1β proving a central role for NF-κB. We conclude that NF-κB is active in myocytes in both the upper and lower segment of the uterus prior to the onset of labour at term and principally regulates a group of immune/inflammation associated genes, demonstrating that myocytes can act as immune as well as contractile cells.
Highlights
Abnormalities of the duration of human pregnancy, resulting in preterm or postdate labour, are major causes of neonatal morbidity and mortality [1, 2]
No significant differences were detected in total p65 protein expression between tissues derived before (n ϭ 11) or after (n ϭ 11) labour onset in lower segment (LS) myometrium, as assessed by Western immunoblot analysis
This study has shown that that nuclear factor-B (NF-B) is active in myocytes in both the upper and lower segment of the uterus prior to the onset of labour at term and regulates principally a group of immune/ inflammation associated genes, demonstrating that myocytes can act as immune as well as contractile cells
Summary
Abnormalities of the duration of human pregnancy, resulting in preterm or postdate labour, are major causes of neonatal morbidity and mortality [1, 2]. Most studies of labour-associated gene expression in myometrium have used lower-segment myometrial biopsies and have shown up-regulation of NF-B regulated genes such as cyclooxygenase (COX)-2, interleukin (IL)-8 and chemokines in the lower segment of the uterus beginning before the onset labour [10, 18, 19]. This suggests that activation of NFB occurs in both upper and lower segment of the uterus at the time of the onset of labour. We validated the array and pathway data by using a combined overexpression and siRNA knockdown approach
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