TIPE2 Play a Negative Role in TLR4-Mediated Autoimmune T Helper 17 Cell Responses in Patients with Myasthenia Gravis
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Th17-related cytokines have been suggested to play a crucial role in myasthenia gravis (MG) pathogenesis.The tumor necrosis factor (TNF)-α-induced protein 8-like-2 (TNFAIP8L2 or TIPE2), is a newly identified member of the tumor necrosis TNFAIP8 family which is an essential negative regulator of both innate and adaptive immunity. In the present study, the expression of TIPE2 mRNA and protein in peripheral blood mononuclear cells (PBMC) from healthy and MG subjects were detected by Real-time PCR and Western blotting.The serum IL-6, IL-17 and IL-21 levels were tested by ELISA. Furthermore, PBMC from MG patients were purified and stimulated with LPS (TLR4 agonist) with or without transfection of TIPE2 expressing adenovirus, then the expression of TIPE2 and Th17-specific transcriptional factor RORγt and the IL-6, IL-17 and IL-21 levels of supernatant were analized. Our data demonstrated that the expression of TIPE2 mRNA and protein was reduced in MG compared with normal controls, with lower expression in generalized patients than in ocular ones. Furthermore, TIPE2 mRNA presents a significantly negative correlation with the serum levels of IL-6, IL-17 and IL-21 in either generalized patients or ocular patients. In cultured MG PBMC, TLR4 activation led to the down-regulation of TIPE2, while the expression of RORγt and production of IL-6, IL-17 and IL-21 were significantly increased. However, when TIPE2 was overexpressed, these TLR4 activation-induced effects were significantly abrogated. Overall, our results indicated for the first time that TIPE2 may participate in the development of MG through negatively regulation of TLR4-mediated autoimmune T helper 17 cell responses.
KeywordsTIPE2 Myasthenia gravis Th17-related cytokines TLR4
Compliance with Ethical Standards
This study was funded by National Nature Science Foundation of China (81571579, 81072465), Natural Science Fund of the Educational Committee of Jiangsu Province (10KJD320003), Special foundation of president of the Xuzhou Medical College (2010KJZ01), Key medical talents fund of Jiangsu Province (H201130), Jiangsu Province ordinary university postgraduate research innovation fund (CXLX11_0734).
Conflict of Interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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