Th2 Cells and Th17 Cells in the Development of Endometriosis – Possible Roles of Interleukin-4 and Interleukin-17A

Abstract

Endometriosis is recognized as an inflammatory disease in which inflammatory cytokines, such as interleukin (IL)-1β and TNFα, play important roles. Immunological factors are also suggested to be involved in the pathogenesis of endometriosis. This review provides comprehensive knowledge about helper T cell (Th cell) and its specific cytokines in endometriosis. A series of our studies demonstrated the presence of Th2 cells and Th17 cells in endometriotic tissues and revealed multiple effects of IL-4 and IL-17A, cytokines secreted from respective Th cells. IL-1β induces secretion of thymic stromal lymphopoietin (TSLP), a regulator for differentiation of inflammatory Th2 cells, in endometriotic stromal cells (ESCs). IL-4 stimulates proliferation of ESCs and production of 3β-hydroxysteroid dehydrogenase Type 2, an enzyme in an estrogen production pathway, in ESCs. IL-17A stimulates IL-8 and Gro-α secretion from ESCs and proliferation of ESCs. IL-17A-induced Gro-α promotes neutrophil migration, which may contribute to the presence of neutrophils in endometriotic tissues. IL-17A also increases secretion of CCL20, a chemokine for Th17 cells, from ESCs, which seems to induce migration of Th17 cells to the endometriotic tissues and enhance the effects of IL-17A further. TNFα in combination with IL-17A synergistically enhances secretion of IL-8 and CCL-20, suggesting cooperation of inflammation and Th17 immune response. These findings suggest that IL-4 and IL-17A promote the development of endometriosis through induction of cell proliferation, inflammation, and estrogen production. It is thus also suggested that IL-4 and IL-17A would be a target of treatment of the disease.