Abstract
Objectives
Primary biliary cirrhosis (PBC) is an autoimmune disease, characterized by antimitochondrial antibodies and autoreactive T cells causing destruction of the primary bile ducts. The molecular mechanisms regulating the autoreactive T cells remain elusive. β-Arrestins (βarr) are multifunctional signaling molecules that are crucial to T cell survival. We hypothesized that βarr plays a critical regulatory function in the autoreactive T cells of PBC patients.
Methods
Patients with hepatic biliary cirrhosis (n = 60) were evaluated. Cytokine expression, T cell proliferation, and transcription factors were evaluated to assess regulatory functions in autoreactive T cells from the patient.
Results
Our studies showed that expression of βarr1 was elevated significantly in T lymphocytes from patients with PBC. Moreover, the level of βarr1 mRNA positively correlated with Mayo risk score in PBC patients. Based on modulation of βarr in autoreactive T cell lines, overexpression of βarr1 increased T cell proliferation, augmented interferon production, downregulated activities of nuclear factor κB and AP-1, promoted acetylation of histone H4 in the promoter regions of CD40L, LIGHT, IL-17 and interferon-γ, while downregulating acetylation of histone H4 in the promoter regions of TRAIL, Apo2, and HDAC7A, thereby regulating expression of these genes.
Conclusions
Our findings suggest that βarr1 contributes to the pathogenesis of PBC, having significant implications for novel therapy strategy, further providing information for investigating the mechanisms of autoimmune disease.
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Abbreviations
- βarr 1:
-
β-arrestin 1
- CHiP:
-
chromatin immunoprecipitation
- IFN:
-
interferon
- NF-κB:
-
nuclear factor κB
- PBC:
-
primary biliary cirrhosis
- PBMC:
-
peripheral blood mononuclear cells
- TBIL:
-
total bilirubin
- TC:
-
total cholesterol
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Acknowledgment
We thank Prof. Gang Pei, Dr. Jiuhong Kang, Dr. Chang Liu for suggestive discussion, Dr. Hongyu Yu, Chuanyong Wu, Tingwang Jiang, and Bo Chen for technical assistance. This research was supported by grants from National Science Foundation of China (30772017, 30770997, 30972730, 81072479) and Shanghai Municipal Commission for Science and Technology (08QH14001, 09JC1405400).
Conflict of Interest
The authors claim no conflict of interest that would influence the publication of this work.
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Zhide Hu, Yuanlan Huang, and Yang Liu contribute equally to this work.
Electronic Supplementary Material
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Supplementary Table 1
The primer pairs and probes for FQ-PCR of specific gene (DOC 31 kb)
Supplementary Table 2
The primer pairs and probes for FQ-PCR of promoters of specific gene (DOC 31 kb)
Supplemental Figure 1
Representative RT-FQ-PCR curves for βarr1 mRNA from PBMCs of healthy controls (a), HBV-infected patients (b), and PBC participants in comparison to 18S ribosomal RNA (c). (DOC 1261 kb)
Supplemental 2
Modulation of endogenous βarr1 expression in autoreactive T cell clones by transfecting with plasmids carrying human βarr1 cDNA or specific siRNA. βarr1 expression in autoreactive T cell clones transfected with plasmids carrying either human βarr1 cDNA or specific siRNA was analyzed by Western blotting. Results from a representative experiment were shown. Lanes 1 normal CD3+ T cells, 2 PBC CD3+ T cells, 3 autoreactive T cells before transfection, 4 autoreactive T cells transfected with β-arrestin-1 overexpression plasmid, 5 autoreactive T cells transfected with β-arrestin-1 silencing plasmid (DOC 271 kb)
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Hu, Z., Huang, Y., Liu, Y. et al. β-Arrestin 1 Modulates Functions of Autoimmune T Cells from Primary Biliary Cirrhosis Patients. J Clin Immunol 31, 346–355 (2011). https://doi.org/10.1007/s10875-010-9492-4
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DOI: https://doi.org/10.1007/s10875-010-9492-4