This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mazzeo, D. Articles by Panina-Bordignon, P. Search for Related Content PubMed PubMed Citation Articles by Mazzeo, D. Articles by Panina-Bordignon, P.

Interleukin-12 and Its Free p40 Subunit Regulate Immune Recognition of Endometrial Cells: Potential Role in Endometriosis¹

Roche Milano Ricerche (D.M., F.S., P.P-.B.); II Department of Obstetrics and Gynecology, University of Milan (P.V., M.V.); and Istituto Auxologico Italiano (A.M.D.), Milan, Italy

Address all correspondence and requests for reprints to: Dr. Paola Panina-Bordignon, Roche Milano Ricerche, 20132 Milan, Italy. E-mail: paola.panina{at}roche.com

An alteration of immune recognition and killing of misplaced endometrial cells, refluxed with menstrual debris in ectopic sites, has been claimed to be responsible for the initiation and progression of endometriosis. In particular, current evidence emphasizes the role of natural killer (NK) cells as potential effectors of peritoneal immune surveillance. Interleukin-12 (IL-12), a heterodimeric cytokine composed of p40 and p35 chains, has potent regulatory effects on NK cell growth and function. The purpose of this study was to evaluate whether this cytokine may also have a role in the specific cytolytic NK cell response toward endometrial antigens. To this aim, concentrations of IL-12 and its free p40 subunit were determined in peritoneal fluid of 33 patients with endometriosis and 40 women without laparoscopic evidence of the disease. Similar concentrations of IL-12, but significantly higher levels of free p40, were present in peritoneal fluid of patients with endometriosis compared to those in women without the disease. We also observed that the IL-12 plus free p40/IL-12 ratio increased with the severity of the disease. Moreover, we investigated whether incubation of NK cells with heterodimeric IL-12 and/or p40 has any effect on NK cell-mediated lysis of endometrial cells. NK cells pretreated with heterodimeric IL-12 exhibited an enhanced cytotoxic response toward endometrial targets. This IL-12-induced cytotoxicity could be abrogated by the p40 subunit in a specific and dose-dependent manner. The p40 inhibitory effect was mediated by down-regulation of IL-12 high affinity binding sites on NK cells, as we observed inhibition of surface IL-12 receptor ß1-chain expression, a decrease in IL-12-binding capacity, and inhibition of phosphorylation of STAT4 (signal transducer and activator of transcription) protein. These data suggest that the excess of p40 present in peritoneal fluid of patients with endometriosis may be related to the NK cell defect associated with the disease. Moreover, IL-12 could be a potential specific agent able to correct the p40-induced defect in vivo.

This article has been cited by other articles:

				A.G. Braundmeier and A.T. Fazleabas The non-human primate model of endometriosis: research and implications for fecundity Mol. Hum. Reprod., October 1, 2009; 15(10): 577 - 586. [Abstract] [Full Text] [PDF]

				R. Li, X. Luo, Q. Pan, I. Zineh, D. F. Archer, R.S. Williams, and N. Chegini Doxycycline alters the expression of inflammatory and immune-related cytokines and chemokines in human endometrial cells: implication in irregular uterine bleeding Hum. Reprod., October 1, 2006; 21(10): 2555 - 2563. [Abstract] [Full Text] [PDF]

				F Arcuri, M Cintorino, A Carducci, S Papa, M G Riparbelli, S Mangioni, A M Di Blasio, P Tosi, and P Vigano Human decidual natural killer cells as a source and target of macrophage migration inhibitory factor Reproduction, January 1, 2006; 131(1): 175 - 182. [Abstract] [Full Text] [PDF]

				M. Eriksson, S. K. Meadows, C. R. Wira, and C. L. Sentman Unique phenotype of human uterine NK cells and their regulation by endogenous TGF-{beta} J. Leukoc. Biol., September 1, 2004; 76(3): 667 - 675. [Abstract] [Full Text] [PDF]

				P. Vigano, B. Gaffuri, E. Somigliana, M. Infantino, M. Vignali, and A.M. Di Blasio Interleukin-10 is produced by human uterine natural killer cells but does not affect their production of interferon-{gamma} Mol. Hum. Reprod., October 1, 2001; 7(10): 971 - 977. [Abstract] [Full Text] [PDF]

				P. Kalinski, P. L. Vieira, J. H. N. Schuitemaker, E. C. de Jong, and M. L. Kapsenberg Prostaglandin E2 is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer Blood, June 1, 2001; 97(11): 3466 - 3469. [Abstract] [Full Text] [PDF]

				E. Somigliana, P. Vigano, G. Rossi, S. Carinelli, M. Vignali, and P. Panina-Bordignon Endometrial ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis Hum. Reprod., December 1, 1999; 14(12): 2944 - 2950. [Abstract] [Full Text] [PDF]