Interleukin-6 Downregulates T Helper 17 Cytokines via Indoleamine 2,3-Dioxygenase 1 at the Maternal-Fetal Interface

The cytokines interleukin (IL)-6 and transforming growth factor-beta (TGF-β) are established inducers of pathogenic T helper 17 (Th17) cells from naïve T cells. In the maternal-fetal compartment, IL-6 signaling elevates levels of indoleamine 2,3-dioxygenase 1 (IDO1). This study investigated whether IL-6 regulates Th17 cytokine production through IDO1.

Human decidua and chorionic villi (HDCV) were collected from normal early pregnant women undergoing elective termination. For HDCV culture, explants were treated with increasing doses of IL-6 (0-50 ng/mL) or co-treated with IL-6 and the IDO1 inhibitor 1-methyltryptophan (1-MT) for 24 h. HDCV were also treated with IL-6 (5 ng/mL) alone or in combination with TGF-β (0.01-0.1 ng/mL) for 24 h. Recurrent pregnancy loss (RPL) mice were intraperitoneally injected with IL-6 (2, 10, or 50 ng/mL), alone or combined with 1-MT and/or Cosentyx, from gestational day (GD) 0.5 to 8. Protein expression levels of IL-6, IDO1, IL-17, and IL-22 were assessed by Western blotting and immunohistochemistry. Embryo absorption rate (EAR) was calculated on GD 12.5. Cytokine concentrations in supernatants or serum were measured using enzyme-linked immunosorbent assay.

In HDCV tissues, IL-6 positively correlated with IDO1 and negatively correlated with IL-17/IL-22. Exogenous IL-6 dose-dependently upregulated IDO1 and suppressed IL-17/IL-22 in cultured explants, effects reversed by 1-MT. Physiological TGF-β1 (0.01-0.1 ng/mL) enhanced IL-6-induced IDO1 upregulation and Th17 cytokine suppression. In RPL mice, IL-6 reduced EAR and placental IL-17/IL-22 expression while increasing IDO1; these effects were blocked by 1-MT and restored by Cosentyx.

During normal pregnancy, IL-6 alone or the combination of IL-6 and TGF-β at the maternal-fetal interface may inhibit Th17 cytokine production by upregulating IDO1 expression, thereby maintaining pregnancy stability.