Prokineticin 2 promotes endoplasmic reticulum stress in rheumatoid arthritis by potentiating IL-1β-induced inflammation.

OBJECTIVES

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent synovial inflammation and progressive joint destruction. Although current therapies have greatly improved disease management, many patients show an inadequate response or develop resistance to existing therapies. Therefore, identifying novel molecular targets remains essential to improve therapeutic outcomes, particularly in refractory cases.

METHODS

Commercially available rheumatoid arthritis-derived fibroblast-like synoviocytes (RA-FLS) were stimulated with pro-inflammatory cytokines, including interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), to evaluate cytokine-induced gene expression changes. Gene set enrichment analysis (GSEA) and functional assays were used to explore signalling pathways regulated by the candidate gene prokineticin 2 (PK2). Expression of pathway-related markers was validated by qRT-PCR and Western blotting. The in vivo role of PK2 was further assessed in a collagen-induced arthritis (CIA) mouse model.

RESULTS

PK2 expression was significantly increased in synovial tissue from RA patients. In vitro, IL-1β and TNF-α upregulated PK2 expression in RA-FLS. Transcriptomic analysis showed that co-stimulation with PK2 and IL-1β significantly enriched pathways involved in protein processing in the endoplasmic reticulum. Further experiments demonstrated that combined PK2 and IL-1β stimulation increased the expression of XBP1, GRP78, CHOP, and HSPA6. In vivo, PK2 aggravated joint inflammation and tissue damage in CIA mice, whereas the PK2 antagonist PKRA7 significantly alleviated disease severity.

CONCLUSIONS

PK2 is a key RA-associated gene that is closely involved in endoplasmic reticulum protein-processing pathways. Targeting PK2-mediated ER stress may represent a promising therapeutic strategy for RA.