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Abstract Number: 990

Guanylate Binding Protein 5 (GBP5) Inhibits Rheumatoid Arthritis Synovial Fibroblast Mediated Inflammation and Tissue Destruction

Mahamudul Haque1, Anil K. Singh1 and Salahuddin Ahmed1,2, 1Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy, Spokane, WA, 2Division of Rheumatology, University of Washington, Division of Rheumatology, School of Medicine, Seattle, WA

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Fibroblasts, Inflammation, interleukins (IL), matrix metalloproteinase (MMP) and rheumatoid arthritis (RA)

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Session Information

Date: Monday, October 22, 2018

Session Title: Cytokines and Cell Trafficking Poster

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Guanylate binding protein 5 (GBP5), an interferon gamma (IFN-γ) inducible protein, helps to defend against invading pathogens. However, its role and properties beyond anti-viral or anti-bacterial action remains unknown. In the present study, we evaluated the role of GBP5 and its corroboration with IFN-γ in regulating rheumatoid arthritis synovial fibroblast (RASF) mediated inflammation and tissue destruction.

Methods: Cell lysates from RASFs and non-diseased SFs (NLSFs) were prepared to evaluate the expression levels of GBP5 using Western immunoblotting and qRT-PCR methods. siRNA mediated knockdown of GBP5 was conducted to study its effect on IFN-γ (10 ng/ml), IL-1β (10 ng/ml) and/or TNF-α (20 ng/ml)-induced downstream signaling pathway in RASFs. Conditioned media was used to quantitate IL-6, IL-8, matrix metalloproteinase-1 (MMP-1), and CXCL5 production by ELISA. The lentiviral delivery method was used to overexpress GBP5 to evaluate its potential regulatory effects in RASFs.

Results: Our Western blot analysis showed that the expression of GBP5 is significantly reduced in RASFs compared to NLSFs (p<0.05; n=6). We observed a higher expression of GBP5 upon IFN-γ stimulation and the expression was further augmented with IL-1β stimulation (p<0.05; n=6). Co-treatment of RASFs with IFN-γ significantly downregulated IL-1β-induced IL-6, IL-8, and MMP-1 production in RASFs (p<0.05; n=3). To our surprise, siRNA-mediated knockdown of GBP5 reduced the inhibitory potential of IFN-γ and resulted in further upregulation of IL-1β-induced IL-6, IL-8, MMP-1, and CXCL5 production by 84%, 66%, 8-fold, and 72%, respectively (p<0.05; n=3). Evaluating the impact of GBP5 knockdown on the RASF signaling pathways, we observed that GBP5 knockdown in human RASFs selectively amplified the constitutive as well as IL-1β-induced phosphorylation of ERK1/2 and JNK mitogen-activated protein kinases, which are important mediators of inflammation and tissue destruction in RA. Intriguingly, lentivirus-mediated restoration of GBP5 abrogated IL-1β-induced proinflammatory cytokine production, suggesting that GBP5 plays an anti-inflammatory role by inhibiting RASF mediated inflammation.

Conclusion: Our findings suggest that the lack of GBP5 contributes to synovial inflammation, and its restoration suppresses RASF-mediated inflammation and tissue destruction.


Disclosure: M. Haque, None; A. K. Singh, None; S. Ahmed, None.

To cite this abstract in AMA style:

Haque M, Singh AK, Ahmed S. Guanylate Binding Protein 5 (GBP5) Inhibits Rheumatoid Arthritis Synovial Fibroblast Mediated Inflammation and Tissue Destruction [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/guanylate-binding-protein-5-gbp5-inhibits-rheumatoid-arthritis-synovial-fibroblast-mediated-inflammation-and-tissue-destruction/. Accessed January 27, 2023.
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