INTERLEUKIN-12 AND ITS FREE P40 SUBUNIT REGULATE IMMUNE RECOGNITION OF ENDOMETRIAL CELLS - POTENTIAL ROLE IN ENDOMETRIOSIS

An alteration of immune recognition and killing of misplaced endometri al cells, refluxed with menstrual debris in ectopic sites, has been cl aimed to be responsible for the initiation and progression of endometr iosis. In particular, current evidence emphasizes the role of natural killer (NK) cells as potential effecters of peritoneal immune surveill ance. Interleukin-12 (IL-12), a heterodimeric cytokine composed of p40 and p35 chains, has potent regulatory effects on NK cell growth and f unction. The purpose of this study was to evaluate whether this cytoki ne may also have a role in the specific cytolytic NK cell response tow ard endometrial antigens. To this aim, concentrations of IL-12 and its free p40 subunit were determined in peritoneal fluid of 33 patients w ith endometriosis and 40 women without laparoscopic evidence of the di sease. Similar concentrations of IL-12, but significantly higher level s of free p40, were present in peritoneal fluid of patients with endom etriosis compared to those in women without the disease. We also obser ved that the IL-12 plus free p40/IL-12 ratio increased with the severi ty of the disease. Moreover, we investigated whether incubation of NK cells with heterodimeric IL-12 and/or p40 has any effect on NK cell-me diated lysis of endometrial cells. NK cells pretreated with heterodime ric 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 e ffect was mediated by down-regulation of IL-12 high affinity binding s ites on NK cells, as we observed inhibition of surface IL-12 receptor beta 1-chain expression, a decrease in IL-12-binding capacity, and inh ibition of phosphorylation of STAT4 (signal transducer and activator o f transcription) protein. These data suggest that the excess of p40 pr esent in peritoneal fluid of patients with endometriosis may be relate d to the NK cell defect associated with the disease. Moreover, IL-12 c ould be a potential specific agent able to correct the p40-induced def ect in vivo.