Abstract / Summary
Endometriosis is an estrogen-dependent chronic disease characterized by the growth and migration of endometriotic tissue. Various growth factors, cytokines and tight junction proteins, contribute to the progression of endometriosis; however, the mechanisms underlying the chronic inflammation remain unclear. In the present study, by using in vitro models of human cells, we studied novel pathogenesis, the understanding which might be useful in therapy for endometriosis. We used human endometrial epithelial （HEME） cells and stromal （HEMS） cells derived from endometriotic tissue, and human endometrioid endometrial cancer cell line Sawano. Treatments with the TGF-β family, TGF-β and activin A, an inhibitor of Rho and ROCK inhibitor signaling Y27632, cytokines TNFα, IL-6, IL-17 and IL-22, induced cell migration, invasion, proliferation and metabolism. In some treated HEME and Sawano cells, changes in the expression of tight junction proteins LSR, TRIC and CLDN-1 were observed. Furthermore, in 2.5D cultures of Sawano cells, treatments with activin A, IL-6, IL-17 and IL-22 induced epithelial permeability. The changes induced by all treatments were prevented by not only various signaling inhibitors, MAPK inhibitor U0126, MST1/2 inhibitor XMU-MP-1, proline-rich tyrosine kinase 2 （PYK2） inhibitor PF431396, and glutaminase 1 （GLS1） inhibitor BPTES but also by antibodies for several cytokines, including an anti-IL-6 antibody （siltuximab）, anti-TNFα antibody （infliximab）, and anti-IL-22 antibody （fezakinumab）. Our results suggest that non-hormonal drugs, signaling inhibitors and cytokine antibodies can prevent the progression of human endometriosis.