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

Daniela Mazzeo, D Mazzeo, Paola Viganò, P Viganó, A M Di Blasio, F Sinigaglia, Francesco Sinigaglia, M Vignali, Paola Panina‐Bordignon, P Panina-Bordignon
The Journal of clinical endocrinology and metabolism · 1998 · vol. 83(3) , pp. 911–916 · doi:10.1210/jcem.83.3.4612 · PMID:9506747 · W2091539467
article OA: bronze CC0 ⤵ 41 in-corpus citations
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This study found that excess free IL-12 p40 subunit in peritoneal fluid of endometriosis patients inhibits NK cell killing of endometrial cells, while heterodimeric IL-12 enhances it.

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Abstract

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 beta1-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.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometrium Immune System Interleukin-12 Ascitic Fluid Ascitic Fluid Cells, Cultured DNA-Binding Proteins DNA-Binding Proteins Down-Regulation Down-Regulation Endometriosis Endometrium Endometrium Endometrium Female Humans Immune System Interleukin-12 Interleukin-12

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