NF-κB regulates a cassette of immune/inflammatory genes in human pregnant myometrium at term.
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.
Khanjani
Shirin
S
Parturition Research Group, Imperial College London, Institute of Reproductive and Developmental Biology, London, UK. S.Khanjani@imperial.ac.uk
Kandola
Mandeep K
MK
Lindstrom
Tamsin M
TM
Sooranna
Suren R
SR
Melchionda
Manuela
M
Lee
Yun S
YS
Terzidou
Vasso
V
Johnson
Mark R
MR
Bennett
Phillip R
PR
D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000276:immunology*; D053583:Interleukin-1beta / Q000494:pharmacology; D007743:Labor, Obstetric / Q000187:drug effects / Q000235:genetics; D009215:Myometrium / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015203:Reproducibility of Results; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA
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