Thalidomide inhibits tumor necrosis factor-alpha-induced interleukin-8 expression in endometriotic stromal cells, possibly through suppression of nuclear factor-kappaB activation.
OBJECTIVE
Endometriosis, a common disease among women of reproductive age, is characterized by the presence of endometrial-like tissue outside the uterus. TNF-alpha induces IL-8 production in endometriotic cells through nuclear factor-kappaB (NF-kappaB) activation. Thalidomide (Thal) inhibits inflammation by down-regulating the expression of proinflammatory cytokines in tumor cells and inflammatory cells. However, the mechanism of Thal action in human endometriotic stromal cells has not yet been elucidated.


METHODS
We examined whether Thal abrogates TNF-alpha-induced up-regulation of IL-8 expression in endometriotic stromal cells.


RESULTS
Here, we show 1) that treatment of endometriotic stromal cells with TNF-alpha increased the expression of phosphorylated IkappaBalpha and degradation of total IkappaBalpha, which in turn activates NF-kappaB; 2) Thal significantly inhibits the TNF-alpha-induced expression of phosphorylated IkappaBalpha and degradation of IkappaBalpha; 3) TNF-alpha activation induced increased nuclear translocation of NF-kappaB, which was inhibited by pretreatment with either Thal or N-tosyl-L-phenylalanine chloromethyl ketone, an NF-kappaB inhibitor. Thal did not enhance the N-tosyl-L-phenylalanine chloromethyl ketone's action; and 4) Pretreatment with Thal reduced TNF-alpha-induced IL-8 protein production as well as mRNA expression.


CONCLUSIONS
The current study showed for the first time that Thal treatment attenuated the expression of IL-8 by reducing TNF-alpha-induced NF-kappaB activation.
Yagyu
Tatsuo
T
NetForce Co. Ltd., Nagoya, Aichi, Japan.
Kobayashi
Hiroshi
H
Matsuzaki
Hidenori
H
Wakahara
Kiyoshi
K
Kondo
Toshiharu
T
Kurita
Noriyuki
N
Sekino
Hideo
H
Inagaki
Kiyokazu
K
Suzuki
Mika
M
Kanayama
Naohiro
N
Terao
Toshihiko
T
D021581:Active Transport, Cell Nucleus; D002478:Cells, Cultured; D004715:Endometriosis / Q000378:metabolism*; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors*; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D000072000:NF-KappaB Inhibitor alpha; D017154:Stromal Cells / Q000378:metabolism; D013792:Thalidomide / Q000494:pharmacology*; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D020672:I-kappa B Proteins; D016209:Interleukin-8; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D014108:Tosylphenylalanyl Chloromethyl Ketone; D013792:Thalidomide