PARP-2 acts on ILK signaling and pharmacological targeting of PARP-2 ameliorate endometriosis in a mouse model.

Endometriosis, an endocrine disorder in reproductive-aged women with an occurrence of ∼10 %, gives rise to inflammation, pelvic pain, menstrual irregularity, infertility, etc. One study demonstrated the elevated plasma level of PARP during endometriosis. Thus, we studied the role of PARP-2 during endometriosis using human endometriotic tissue and cells along with an endometriosis mouse model. We found an increased expression level of PARP-2 in the endometriotic tissue from human endometriosis patients, likewise in the endometriotic cells, 12Z and mouse model. The expression level of PARP-2 was suppressed by progesterone (P4) in the immortalized human endometriotic cells (IHECs). However, the danazol (100 mg/kg body weight) treatment reduced the lesion size, but not the expression level of PARP-2 in the endometriotic lesion from the mouse model. PARP-2 inhibition by UPF-1069 (5 mg/kg b. wt.) treatment in the mouse model of endometriosis reduced the endometriotic lesion area. During ovulation and letrozole (1 mg/kg b.wt.) treatment in the endometriosis SD rat model, the expression level of PARP-2 was high. The cell aggregation, a spheroid formation assay using IHECs was reduced by PARP-2 inhibition. The inflammatory chemokines, CCL-11 and -22, GSK-3beta and ILK were downregulated in IHECs by PARP-2 inhibitor (10 μM). Transient overexpression of ILK in endometriotic cells showed reduced levels of PARP-2 and GSK-3beta. In conclusion, PARP-2 is upregulated in the endometriotic tissue in response to estradiol (E2) and inhibition of it pharmacologically reduced the IHECs congregation and the endometriotic lesion, possibly affecting the inflammatory response via ILK-GSK-3beta, in the mouse model and human endometriotic cells.