Whether full‐length IL‐38 acts as a promoter or inhibitor in activating rheumatoid arthritis fibroblast‐like synoviocytes depends on IL‐1β

Abstract

AimIL‐38 is a recently discovered inflammatory factor that belongs to the IL‐1 family and has full‐length and truncated forms. Clinical findings demonstrated that serum IL‐38 levels in people with infectious and autoimmune diseases are significantly different from those in healthy people, but the form remains unclear. We are keenly interested in learning more about the regulatory role of full‐length IL‐38 in rheumatoid arthritis (RA), a classic autoimmune disease.MethodsRA‐fibroblast‐like synoviocytes (RA‐FLS) were isolated from six RA patients and stimulated with full‐length IL‐38 to observe IL‐6 and IL‐8 secretion. Then, the migration and invasion functions of FLS were assessed. Next, the protein expressions of the MAPK, NF‐κB, and JAK pathways were evaluated. In addition, we examined the effect of full‐length IL‐38 on FLS functions in the presence of IL‐1β. The function of FLS affected by full‐length IL‐38 was also examined after blocking IL‐1 and IL‐36 receptors.ResultsThe functions of FLS were activated after the cells were stimulated with full‐length IL‐38. IL‐6 and IL‐8 levels increased with an increase in the full‐length IL‐38 concentration, and full‐length IL‐38 induced the acceleration of FLS migration and invasion functions. In addition, the levels of proteins in the MAPK signaling pathway increased after stimulation with full‐length IL‐38 and depended on its concentration. However, when the FLS were stimulated by IL‐38 and IL‐1β simultaneously, all experiments generated opposite results. Full‐length IL‐38 inhibited FLS function in the presence of IL‐1β. IL‐1R and IL‐36R blockers terminated all effects of full‐length IL‐38 on RA‐FLS.ConclusionFull‐length IL‐38 activates FLS functions and acts as a promoter in RA, whereas it inhibits FLS functions and acts as an inhibitor of RA in the presence of IL‐1β. The function of full‐length IL‐38 can be blocked by IL‐1Ra and IL‐36Ra.

Role of IL-1 Family Cytokines IL-36, IL-37, IL-38 in Osteoarthritis and Rheumatoid Arthritis: A Comprehensive Review

“…Rheumatoid arthritis-FLSs treated with full-length IL-38 promoted the activation of ERK, JNK, and P38, and accelerated RA-FLSs migration and invasion. 99 In contrast, RA-FLSs treated with IL-1β showed less expression of IL-6 and IL-8, inhibited activation of ERK, JNK, and P38, and suppressed RA-FLSs migration and invasion. Addition of full-length IL-38 suppressed IL-1β-induced effects on RA-FLSs, suggesting that full-length IL-38 may act as a promoter in RA by regulating IL-1β.…”

“…Addition of full-length IL-38 suppressed IL-1β-induced effects on RA-FLSs, suggesting that full-length IL-38 may act as a promoter in RA by regulating IL-1β. 99 Overexpression of IL-38 gene in synoviocytes promotes cellular proliferation, migration, and invasion and inhibits LC3-II accumulation. 90 Autophagy inhibitor-stimulated cells showed greater migration and invasion, whereas autophagy inducer-stimulated cells showed less migration and invasion.…”