Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells

We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.

Epithelial ovarian cancer is the commonest cause of gynaecological cancer-associated death. The disease typically presents in postmenopausal women, with a few months of abdominal pain and distension. Most women have advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stage III), for which the standard of care remains surgery and platinum-based cytotoxic chemotherapy. Although this treatment can be curative for most patients with early stage disease, most women with advanced disease will develop many episodes of recurrent disease with progressively shorter disease-free intervals. These episodes culminate in chemoresistance and ultimately bowel obstruction, the most frequent cause of death. For women whose disease continues to respond to platinum-based drugs, the disease can often be controlled for 5 years or more. Targeted treatments such as antiangiogenic drugs or poly (ADP-ribose) polymerase inhibitors offer potential for improved survival. The efficacy of screening, designed to detect the disease at an earlier and curable stage remains unproven, with key results expected in 2015. Copyright © 2014 Elsevier Ltd. All rights reserved.

This review focuses on the biology of T helper 17 (Th17) and regulatory T (Treg) cells and their role in inflammatory diseases, such as rheumatoid arthritis. Th17 cells represent a pro-inflammatory subset whereas Treg cells have an antagonist effect. Their developmental pathways are reciprocally interconnected and there is an important plasticity between Th17 and Treg cells. These features implicate that the Th17/Treg balance plays a major role in the development and the disease outcomes of animal model and human autoimmune/inflammatory diseases. During these diseases, this balance is disturbed and this promotes the maintenance of inflammation. Targeting the Th17/Treg imbalance can be performed at different levels such as inhibition of pro-inflammatory cytokines and their receptors, of pathogenic cells or their specific signaling pathways. Conversely, direct effects include administration or induction of protective cells, or stimulation of their specific pathways. Several clinical trials are underway and some positive results have been obtained. Copyright © 2014 Elsevier B.V. All rights reserved.