Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut, USA
Address for correspondence: Aydin Arici, M.D., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8063. Voice: 203-785-4005; fax: 203-785-7134.
aydin.arici{at}yale.edu
Endometriosis, defined by the presence of viable endometrial
tissue outside the uterine cavity, is among the most common
gynecologic disorders affecting women of reproductive age. Endometriosis
is associated with an inflammatory peritoneal environment, where
multiple cytokines and growth factors are found at elevated
levels. Interleukin-8 (IL-8) is a cytokine that induces chemotaxis
of neutrophils and is a potent angiogenic agent. In addition,
IL-8 was recently found to stimulate proliferation of various
cells. We have observed that IL-8 is elevated in the peritoneal
fluid of women with endometriosis and the levels correlate with
the severity of the disease. We hypothesized that IL-8 may play
a role in the growth and maintenance of ectopic endometrial
tissue not only by chemoattracting and stimulating leukocytes
to secrete growth factors and cytokines, but also by directly
affecting endometrial cell proliferation. We found that IL-8
mRNA and protein levels in the endometrium were significantly
higher during early proliferative and late secretory phases
than during the mid-cycle. IL-8 receptors A and B are also expressed
in the endometrium mostly localized in the stroma. Interestingly,
IL-8 receptor expression is higher in the eutopic endometrium
of women with endometriosis compared to the endometrium of women
without endometriosis. Endometrial cells in culture proliferate
significantly when treated with IL-8, which is inhibited by
anti-IL-8 neutralizing antibody. More convincingly, IL-8 antisense
oligonucleotide treatment decreases IL-8 production by endometrial
cells as well as cell proliferation when compared to non-sense
oligonucleotide treatment. The addition of IL-8 reverses the
inhibitory effect of IL-8 antisense oligonucleotides on cell
proliferation. These findings suggest that IL-8 may act as an
autocrine growth factor in the endometrium. We have also studied
the effect of endometrial cell adhesion on IL-8 expression and
observed that IL-8 stimulates the adhesion of endometrial cells
to fibronectin. Treatment of the cells with anti-IL-8 neutralizing
antibody inhibited partially the cell adhesion. Thus, IL-8 may
also be relevant for stimulating the attachment of endometrial
implants in the pathogenesis of endometriosis. In addition,
adherence of endometrial cells induced further IL-8 expression
by an integrin-dependent mechanism. In summary, IL-8 may act
as an autocrine growth factor in the endometrium and may also
play a role in the pathogenesis of endometriosis by promoting
the vicious circle of endometrial cell attachment, cell growth,
and further secretion of this cytokine.
