Interleukin 8 production and interleukin 8 receptor expression in human myometrium and leiomyoma.
OBJECTIVE
Interleukin 8 is a potent chemoattractant cytokine that is expressed in a variety of human tumors and is known to induce mitogenesis. We aimed to investigate the production of interleukin 8 and the expression of its receptor in myometrium and leiomyoma, in which we hypothesized that interleukin 8 may contribute to cellular proliferation.


METHODS
Myometrial and leiomyoma tissue pairs (n = 14) were obtained from human uteri after hysterectomy conducted for leiomyomatous uterus. Expression of interleukin 8 and interleukin 8 receptor type A was identified in the leiomyomatous myometrium by means of specific antibodies directed against interleukin 8 and interleukin 8 receptor type A for immunohistochemical detection. Interleukin 8 production by cultured cells was measured by enzyme-linked immunosorbent assay. The regulation of interleukin 8 messenger ribonucleic acid expression was assessed by means of the Northern blot analysis after treatment of myometrial cells with interleukin 1alpha and tumor necrosis factor alpha. Myometrial cell proliferation was determined by means of colorimetric assay after cells were treated with interleukin 8 and antihuman interleukin 8 neutralizing antibody.


RESULTS
Immunostaining for both interleukin 8 and interleukin 8 receptor type A was stronger in the myometrium adjacent to leiomyoma compared with leiomyoma itself (2-fold, P <.05). Compared with samples from nonusers, samples from patients who had used gonadotropin-releasing hormone agonists revealed a trend for decreased staining for both interleukin 8 and interleukin 8 receptor type A. Interleukin 1alpha and tumor necrosis factor alpha caused a time- and dose-dependent increase in interleukin 8 production by myometrial cells (P <.001). There was a dose-dependent inhibition of cell proliferation with antihuman interleukin 8 antibody to 55% of the control (P <.001).


CONCLUSIONS
Our demonstration of high levels of interleukin 8 and its receptor in myometrium immediately surrounding leiomyoma and the inhibition of cell proliferation when interleukin 8 is blocked by a neutralizing antibody suggest a potential role for interleukin 8 in the growth of myometrial tissue surrounding leiomyomatous tissue. This study could lead to a better understanding of potential involvement of cytokines in leiomyoma growth and in gonadatropin-releasing hormone agonist-induced regression.
Senturk
L M
LM
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.
Sozen
I
I
Gutierrez
L
L
Arici
A
A
D015152:Blotting, Northern; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D007700:Kinetics; D007889:Leiomyoma / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D009215:Myometrium / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D023062:Receptors, Interleukin-8A / Q000032:analysis*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014594:Uterine Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology
D007375:Interleukin-1; D016209:Interleukin-8; D012333:RNA, Messenger; D023062:Receptors, Interleukin-8A; D014409:Tumor Necrosis Factor-alpha; D007987:Gonadotropin-Releasing Hormone