Abstract | OBJECTIVE: METHODS: Activation of Pin1 and TLR-7/TLR-9/IRAK-1/IRF-7 signaling was determined in various cell types among peripheral blood mononuclear cells from healthy controls and SLE patients. The effects of Pin1 and TLR signaling on SLE development were determined using validated Pin1 short hairpin RNA ( shRNA), Pin1 genetic knockout, and the small-molecule Pin1 inhibitor all-trans-retinoic acid (ATRA) in immune cells and in several strains of lupus-prone mice. RESULTS: We found abnormal activation of Pin1 and its downstream targets IRAK-1 and IRF-7 in SLE patients. Furthermore, inhibition of Pin1 using either validated Pin1 shRNA or ATRA blocked TLR-7-induced activation of IRAK-1 and IRF-7 in SLE patient-derived immune cells. Moreover, in multiple lupus-prone animals, both Pin1 knockout and ATRA strikingly attenuated the expression of autoimmunity, including skin lesions, lymphadenopathy, splenomegaly, glomerulonephritis, proteinuria, and production of anti- double-stranded DNA antibodies and CD4-CD8- T cells, and also prolonged overall survival in MRL/lpr and B6.lpr mice. CONCLUSION: Pin1 plays a critical role in the development of SLE, and Pin1-targeted therapy offers a promising new strategy for treating SLE.
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Authors | Shuo Wei, Nobuya Yoshida, Greg Finn, Shingo Kozono, Morris Nechama, Vasileios C Kyttaris, Xiao Zhen Zhou, George C Tsokos, Kun Ping Lu |
Journal | Arthritis & rheumatology (Hoboken, N.J.)
(Arthritis Rheumatol)
Vol. 68
Issue 10
Pg. 2503-13
(10 2016)
ISSN: 2326-5205 [Electronic] United States |
PMID | 27159270
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2016, American College of Rheumatology. |
Chemical References |
- Interferon Regulatory Factor-7
- NIMA-Interacting Peptidylprolyl Isomerase
- RNA, Small Interfering
- Toll-Like Receptor 7
- Toll-Like Receptor 9
- Tretinoin
- Interleukin-1 Receptor-Associated Kinases
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Topics |
- Animals
- Cell Culture Techniques
- Cell Line
- Flow Cytometry
- Gene Knockdown Techniques
- Humans
- Immunoblotting
- In Vitro Techniques
- Interferon Regulatory Factor-7
(drug effects, immunology)
- Interleukin-1 Receptor-Associated Kinases
(drug effects, immunology)
- Leukocytes, Mononuclear
(drug effects, immunology)
- Lupus Erythematosus, Systemic
(drug therapy, immunology)
- Mice
- Mice, Inbred MRL lpr
- Mice, Knockout
- Molecular Targeted Therapy
- Monocytes
(drug effects, immunology)
- NIMA-Interacting Peptidylprolyl Isomerase
(antagonists & inhibitors, genetics, immunology)
- RNA, Small Interfering
(pharmacology)
- Signal Transduction
(drug effects, immunology)
- T-Lymphocytes
(drug effects, immunology)
- Th17 Cells
(drug effects, immunology)
- Toll-Like Receptor 7
(drug effects, immunology)
- Toll-Like Receptor 9
(drug effects, immunology)
- Tretinoin
(pharmacology)
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