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Activated macrophage-like synoviocytes are resistant to endoplasmic reticulum stress-induced apoptosis in antigen-induced arthritis

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Abstract

Objective

To explore the characteristic expression of endoplasmic reticulum (ER) stress protein in antigen-induced arthritis models and the role of ER stress in arthritis.

Methods

Effective animal models of rheumatoid arthritis in rabbits and rats were induced by methylated bovine serum albumin and Freund’s complete adjuvant. Pathological changes were assessed by magnetic resonance imaging and histological analysis. The expression and localization of ER stress proteins in synovium and peritoneal macrophages (PMΦ) were analyzed by double immunofluorescence staining. RT-PCR was performed to detect mRNA expression of ER stress-related genes. Tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels in synoviocytes were measured by RT-PCR and radioimmunoassay.

Results

We found that the ER stress marker BiP was highly up-regulated in arthritis synovium and extensively expressed in fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes (MLS). The expression of the pro-apoptotic factor CHOP/GADD153 was slightly elevated in inflammatory synovium and mainly localized in FLS, but insignificant in MLS. Unexpectedly, increased expression of CHOP was observed in PMΦ in arthritis rats. Likewise, cleaved caspase-3 was rarely expressed in MLS. In addition, induction of ER stress by tunicamycin resulted in significantly increased expression of pro-inflammatory molecules such as IL-1β and TNF-α in cultured inflammatory FLS.

Conclusion

Differential activation of the ER stress proteins in synovium MLS may contribute to the resistance of synoviocytes to ER stress-induced apoptosis. Furthermore, ER stress is a potential mediator of arthritis inflammation.

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Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (No. 81173074, 91129729) to SYX and (No. 81302755) to FLJ, from Research Fund for the Doctoral Program of Higher Education of China (No. 20113420110004, 20123420120002), and supported by Anhui Provincial Natural Science Foundation (11040606Q14) to FLJ.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. School of Basic Medical Science, Anhui Medical University, 69 Meishan Road, 230032, Hefei, China

    Li-Jie Feng, Tong-Cui Jiang & Yu-Xian Shen

  2. Institute of Biopharmaceuticals, Anhui Medical University, 230032, Hefei, China

    Li-Jie Feng, Tong-Cui Jiang, Cheng-Yue Zhou, Yu-Jun Shen & Yu-Xian Shen

  3. Department of Radiology, the First Affiliated Hospital, Anhui Medical University, 230032, Hefei, China

    Chang-Liang Yu

  4. School of Pharmacy, Anhui Medical University, 69 Meishan Road, 230032, Hefei, China

    Cheng-Yue Zhou & Jun Li

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  1. Li-Jie Feng
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Correspondence to Jun Li or Yu-Xian Shen.

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Responsible Editor: Ikuo Morita.

Electronic supplementary material

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Fig S1. Expression of BiP in normal synovium. a–d Double labeling of BiP (green) and α-SMA (red). e–h Double labeling of BiP (green) and CD68 (red). Scale bar = 50 μm.

Fig S2. Expression of CHOP in normal synovium. a–d Double labeling of CHOP (red) and α-SMA (green). e–h Double labeling of CHOP (red) and CD68 (green). Scale bar = 50 μm.

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Feng, LJ., Jiang, TC., Zhou, CY. et al. Activated macrophage-like synoviocytes are resistant to endoplasmic reticulum stress-induced apoptosis in antigen-induced arthritis. Inflamm. Res. 63, 335–346 (2014). https://doi.org/10.1007/s00011-013-0705-1

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  • DOI: https://doi.org/10.1007/s00011-013-0705-1

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