Abstract
Activated T helper 17 (Th-17) cytokines play a role in the pathophysiology of autoimmune and infectious diseases. While these diseases affect many women of childbearing age, little is known about the effect of these cytokines on placental transporters. As several pro-inflammatory cytokines impact the expression of ABC and SLC placental transporters, we hypothesized that these transporters may be similarly altered by elevated levels of circulating Th-17 cytokines. Cultured term human villous explants were treated with IL-17A, IL-22, or IL-23, alone or in combination. Samples were analyzed using qRT-PCR and Western blotting. The mRNA expression of OATP2B1 was significantly downregulated in explants by all individual cytokines and combination treatments, while decreased protein expression was seen with IL-23 and combination (p < 0.01). Combination treatment decreased the mRNA expression of BCRP and OAT4 but increased that of OCT3 (p < 0.01). Decreased accumulation of the OATP substrate, cascade blue, was seen in IL-23-treated choriocarcinoma JAr cells (p < 0.01). Elevated Th-17 cytokines, which are seen in infectious and autoimmune diseases, affect the expression and activity of OATP2B1, as well as mRNA expression of placental BCRP, OAT4, and OCT3. This dysregulation could impact the fetal exposure to endogenous and exogenous substrates.
Highlights
Activated T helper 17 (Th-17) CD4+ cells are major contributors to the pathogenesis of several autoimmune diseases and inflammatory conditions
5-fold higher levels of IL-22 are seen in the serum of patients with autoimmune diseases such as rheumatoid arthritis [5,6], while a 3-fold increase in serum levels of IL-23 has been reported in patients with multiple sclerosis [7]
Recent studies have reported the involvement of Th-17 CD4+ cell activation and IL-17 release in the pathogenesis of the cytokine storm and severe outcomes associated with COVID-19 [8]
Summary
Activated T helper 17 (Th-17) CD4+ cells are major contributors to the pathogenesis of several autoimmune diseases and inflammatory conditions. Expression of IL-17A, IL-22, and IL-23R by activated Th-17 cells, increases the production of pro-inflammatory cytokines and chemokines in target tissues, thereby resulting in systemic inflammatory effects [3,4]. 5-fold higher levels of IL-22 are seen in the serum of patients with autoimmune diseases such as rheumatoid arthritis [5,6], while a 3-fold increase in serum levels of IL-23 has been reported in patients with multiple sclerosis [7]. It is recognized that increased systemic production of pro-inflammatory cytokines due to acute or chronic inflammatory conditions can impact the expression and activity of many clinically important drug metabolizing enzymes and membrane transporters [9,10]
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