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Please use this identifier to cite or link to this item: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/38434

Title: Reversing interleukin-2 inhibition mediated by anti–double-stranded DNA autoantibody ameliorates glomerulonephritis in MRL-lpr/lpr mice
Authors: Ying-Chyi Song;Shye-Jye Tang;Tai-Ping Lee;Wen-Chien Hung;Shu-Chi Lin;Chang-Youh Tsai;Wailap Victor Ng;Ming-Fang Wu;Kuang-Hui Sun
Contributors: 國立臺灣海洋大學:生命科學暨生物科技學系
Date: 2010
Issue Date: 2016-09-01T06:50:16Z
Publisher: Arthritis Rheumatology
Abstract: Abstract:
Objective

Our previous study demonstrated that anti–double-stranded DNA (anti-dsDNA) antibodies involved in lupus nephritis down-regulate the production of interleukin-2 (IL-2) in T cells, which in turn, contributes to the defective production of cytotoxic cells and to activation-induced cell death in vitro. To reveal novel molecular targets for lupus therapy, the molecular mechanisms of IL-2 down-regulation by anti-dsDNA were studied.
Methods

Anti-dsDNA monoclonal antibody (mAb) 9D7 was used to study the molecular mechanisms of IL-2 production in vitro. Treatment with arginine-rich peptide, a penetration inhibitor, was used to verify the effect of internalization of anti-dsDNA on the production of IL-2. The signaling pathway for IL-2 expression induced by anti-dsDNA was analyzed by using kinase inhibitors. The therapeutic effects of these inhibitors were evaluated in MRL-lpr/lpr mice.
Results

Inhibition of IL-2 production in activated Jurkat cells and human T cells pretreated with mAb 9D7 was reversed by treatment with the arginine-rich peptide. Levels of pAkt and phosphorylated glycogen synthase kinase 3 (pGSK-3) were reduced in activated Jurkat cells that had been pretreated with mAb 9D7. The inhibition of IL-2 production by mAb 9D7 was counteracted by pretreating the cells with LiCl (a GSK-3 inhibitor). However, IL-2 reduction was not recovered in the cells pretreated with ERK and JNK inhibitors. Furthermore, MRL-lpr/lpr mice injected with LiCl or with arginine-rich peptide restored the IL-2 production and reduced the manifestations of lupus.
Conclusion

These findings suggest that penetration of T cells by anti-dsDNA may inhibit IL-2 production by activating GSK-3. Moreover, blocking GSK-3 activation as well as inhibiting anti-dsDNA penetration is a potential therapeutic approach for lupus.
Relation: 62(8)
URI: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/38434
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