Estrogen increases, whereas IL-27 and IFN-γ decrease, splenocyte IL-17 production in WT mice

Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060-0342, USA.
European Journal of Immunology (Impact Factor: 4.03). 09/2010; 40(9):2549-56. DOI: 10.1002/eji.201040303
Source: PubMed


Estrogen-mediated regulation of Th1, Th2 and Treg effector functions are well documented but, surprisingly, there is little information whether estrogen modulates IL-17, a powerful proinflammatory cytokine that plays a pivotal role in several inflammatory and autoimmune diseases. Therefore in the current study, we determined whether estrogen regulates the expression levels of IL-17 in WT C57BL/6 mice. By ELISA, ELISPOT and/or flow cytometric analyses, we found that estrogen upregulated the levels of not only IL-17, but also the IL-17-specific transcription factor retinoic acid-related orphan receptor gamma t (ROR gamma t), in activated splenocytes. IL-17 levels were further enhanced by exposure of activated splenocytes to IL-23, particularly in cells from estrogen-treated mice. Exposure of splenocytes to IL-27 or IFN-gamma at the time of activation markedly inhibited the levels of IL-17 and ROR gamma t. Interestingly, a delay of 24 h in exposure of activated splenocytes to IL-27 or IFN-gamma decreased IL-17 levels (albeit less profoundly) but not ROR gamma t. These findings imply that the suppressive effects of IL-27 and IFN-gamma are more effective prior to the differentiation and commitment of IL-17-secreting cells. Furthermore, inhibition of JAK-2 by AG490 suppressed IL-17 but not ROR gamma t expression, suggesting that other transcription factors are also critical in estrogen-mediated upregulation of IL-17.

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    • "Increased expression of these estrogen-inducible proteins in immune cells is associated with the development of SLE (Panchanathan et al., 2009; Mai et al., 2010; Khan et al., 2010; Shen et al., 2010). Notably, BPA-induced signaling in cells interferes with endocrine signaling that regulates a number of immune cell types and their immune functions (Rao and Richardson, 1999; Cooper et al., 2008; Rogers et al., 2013; Kharrazian, 2014). "
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    • "Concerning Th17 cells, it has been shown for a long time that E2 suppresses experimental allergic encephalomyelitis (EAE), a Th17-mediated disease (97, 98), and E2 inhibits IL-17 production by murine lymphocytes (99). On the contrary, Khan et al. found that E2 promotes IL-17 production as well as RORγ expression in stimulated splenocytes in mice (100). Even if those studies revealed contradictory results, they suggest that E2 regulates Th17 cells, perhaps depending on the context. "
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    • "Estrogen also enhances B cell activation (Paavonen, Andersson et al. 1981), IgG production (Kanda and Tamaki 1999), and upregulates activation-induced deaminase (AID), thereby enhancing somatic hypermutation frequency and class-switch recombination, resulting in greater antibody affinity-maturation (Karpuzoglu and Zouali 2011). In vitro studies examining the effect of E2 on T cell proliferation and cytokine production have often yielded contradictory results when using PBMC (Bouman, Heineman et al. 2005) although some observations do suggest a potential bias towards Th2, Th17 (Polanczyk, Hopke et al. 2006) and Treg polarization in E2 treated T cell cultures (Khan, Dai et al. 2010). "

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