TAK1 activation for cytokine synthesis and proliferation of endometriotic cells

Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, Yonago, Japan.
Molecular and Cellular Endocrinology (Impact Factor: 4.41). 06/2009; 307(1-2):196-204. DOI: 10.1016/j.mce.2009.04.012
Source: PubMed


Endometriosis causes pelvic pain and infertility in women of reproductive age. We explored TNFalpha-induced specific signaling pathways and gene expressions in endometriotic stromal cells (ESCs). Based on the data of the pathway specific cDNA array, we analyzed the role of TAK1, which is believed to work as a common mediator for NF-kappaB and MAPK pathways. Using the NF-kappaB pathway array, we found that TNFalpha upregulated ICAM-3, IL-6, IL-8, TAK1, JNK2, RelA, and TLR4 expressions. TNFalpha augmented the phosphorylation of TAK1. By transfection of TAK1 siRNA, TNFalpha-induced phosphorylation of IkappaBalpha, JNK1/2, and p38MAPK, as well as IL-6 or IL-8 expression, were repressed. TAK1 silencing in TNFalpha-pretreated ESCs caused a decrease in the proportion of cells in S-phase, and reduced TNFalpha-promoted BrdU incorporation. We provide the first evidence that TNFalpha and its downstream TAK1, which are key mediators for NF-kappaB and MAPK pathways, may be involved in the pathogenesis of endometriosis.

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    • "BCR and TLR9 costimulation may enhance IL-6, IL-10 and TNFα secretion [44]. The role of TAK1 on cytokine synthesis was demonstrated in TAK1 deficient mice and by TAK1 gene silencing experiments [33], [45]. We addressed the question whether the combined suboptimal anti-Ig, CpG and BAFF stimuli induce a synergistic cytokine production by B cells. "
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    ABSTRACT: To determine whether nuclear factor-kappaB (NF-kappaB) is constitutively and tumor necrosis factor (TNF)-dependently activated in endometriotic cells, whether trichostatin A (TSA) can suppress NF-kappaB activation and suppress TRAF2/6 and TAK1, and whether TSA and caffeic acid phenyl ester can suppress constitutive and H(2)O(2)-stimulated proliferation of endometriotic cells. Two endometriotic cell lines and an endometrial stromal cell line were used as an in vitro model. Electrophoretic mobility shift analysis was used to determine NF-kappaB activation and possible suppression by TSA. Western blot analysis was used to determine whether TSA suppresses phosphorylation of IkappaBalpha, phosphorylation of p65 in the cytoplasm and nuclear translocation, and the expression of TRAF2/6 and TAK1. NF-kappaB was constitutively activated in endometriotic cells, but only minimally in endometrial cells. TNFalpha stimulation activated NF-kappaB through induction of IkappaB phosphorylation, but the activation can be suppressed by TSA. TSA also attenuated constitutive and TNF-dependent p65 phosphorylation and nuclear translocation in endometriotic cells. TRAF2, TRAF6 and TAK1 were constitutively activated and were unaffected by TSA treatment. NF-kappaB activation may play a critical role in the pathogenesis in endometriosis. Targeting NF-kappaB with histone deacetylase inhibitors or other compounds might hold promise as novel therapeutics for endometriosis.
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