Neutralizations of IL-17A and IL-21 regulate regulatory T cell/T-helper 17 imbalance via T-helper 17-associated signaling pathway in immune thrombocytopenia. (June 2015)

• Record Type: Journal Article
• Authors: Hu, Yu; Wang, Xiuwen; Yu, Shuang; Hou, Yu; Ma, Daoxin; Hou, Ming
• Is Part Of: Expert opinion on therapeutic targets. Volume 19:Number 6(2015:Jun.)
• Page Start: 723
• Page End: 732
• Publication Date: 2015-06
• Subjects: Drugs -- Research -- Periodicals; 615.072
• DOI: 10.1517/14728222.2015.1016499
• Languages: English
• ISSNs: 1744-7631

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <p> <bold> <italic>Objective:</italic> </bold> The imbalance of regulatory T cell/T-helper 17 (Treg/Th17) is critical for the pathogenesis of immune thrombocytopenia (ITP) and IL-17A and IL-21 are overexpressed in ITP. The effects and mechanisms of IL-17A and IL-21 in Treg/Th17 imbalance and ITP pathophysiology are not clarified.</p> <p> <bold> <italic>Methods:</italic> </bold> Peripheral blood mononuclear cells (PBMCs) and CD3<sup>+</sup> T cells from ITP patients and healthy controls were treated with cytokines or antibodies to increase or neutralize IL-17A or IL-21 levels for 72 h. Treg/Th17 differentiation, apoptosis, proliferation and Th17 differentiation-associated transcriptional factors were analyzed.</p> <p> <bold> <italic>Results:</italic> </bold> Natural Treg/Th17 decreased in newly diagnosed ITP patients and recovered after remission. IL-17A or IL-21 increased Th17, decreased Tregs and downregulated Treg/Th17 <italic>in vitro.</italic> Conversely, neutralization of IL-17A or IL-21 decreased Th17, increased Tregs and up-regulated Treg/Th17. The reverse effects of IL-17A or IL-21 were mediated by Th17-associated transcriptional factors. IL-17A or IL-21 enhanced STAT-1, STAT-3, STAT-5 or RAR-related orphan receptor C (RORC), whereas anti-IL-17A or anti-IL-21 mAb downregulated STAT-1, STAT-5 or RORC transcripts in ITP PBMCs. Proliferation showed no significant difference. IL-21 inhibited apoptosis in ITP PBMCs.</p> <p> <bold> <italic>Conclusion:</italic> </bold> IL-17A and IL-21 induce Th17 and inhibit Tregs re-differentiation via Th17-associated signaling pathway in ITP patients <italic>in vitro.</italic> It highlights the potential value of IL-17A or IL-21 blockade as a novel therapeutic target for ITP.</p> </abstract>