Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammatory bone destruction in which tumor necrosis factor alpha (TNF-α) plays a key role. Bovine lactoferrin (bLF) is a multifunctional protein with anti-inflammatory and immunomodulatory properties. This study aimed to clarify the inhibitory effects of bLF on the pathological progression of RA. The mannan-induced arthritis model in SKG mice (genetic RA model) was used. Orally applied liposomal bLF (LbLF) markedly reduced ankle joint swelling and bone destruction. Histologically, pannus formation and osteoclastic bone destruction were prevented in the LbLF-treated animals. Moreover, orally administered LbLF improved the balance between Th17 cells and regulatory T cells isolated from the spleen of mannan-treated SKG mice. In an in vitro study, the anti-inflammatory effects of bLF on TNF-α-induced TNF-α production and downstream signaling pathways were analyzed in human synovial fibroblasts from RA patients (RASFs). bLF suppressed TNF-α production from RASFs by inhibiting the nuclear factor kappa B and mitogen-activated protein kinase pathways. The intracellular accumulation of bLF in RASFs increased in an applied bLF dose-dependent manner. Knockdown of the lipoprotein receptor-related protein-1 (LRP1) siRNA gene reduced bLF expression in RASFs, indicating that exogenously applied bLF was mainly internalized through LRP-1. Immunoprecipitated proteins with anti-TNF receptor-associated factor 2 (TRAF2; an adapter protein/ubiquitin ligase) included bLF, indicating that bLF binds directly to the TRAF2-TRADD-RIP complex. This indicates that LbLF may effectively prevent the pathological progression of RA by suppressing TNF-α production by binding to the TRAF2-TRADD-RIP complex from the RASFs in the pannus. Therefore, supplemental administration of LbLF may have a beneficial effect on preventive/therapeutic reagents for RA.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease characterized by continuous inflammation and proliferation of synovial fibroblasts, resulting in irreversible destruction of articular cartilage and bone [1]
We investigated the effects of orally administered liposomal bLF (LbLF) on the pathological progression of RA in SKG mice and clarified the mechanisms underlying the inhibitory effect of bovine lactoferrin (bLF) on tumor necrosis factor α (TNF-α)-induced activation of synovial fibroblasts and osteoclastogenesis
There was no difference in body weight among the experimental groups (S1C Fig), indicating that orally administered LbLF had no harmful effects on mouse health
Summary
Rheumatoid arthritis (RA) is an autoimmune disease characterized by continuous inflammation and proliferation of synovial fibroblasts, resulting in irreversible destruction of articular cartilage and bone [1]. The worldwide prevalence of RA varies between 0.5% and 1%, with RA being more common in women [2]. RA begins with joint stiffness, followed by swelling and pain in the affected joint. RA leads to body dysfunction owing to marked deformity of the joint [3]. The quality of life of patients significantly decreases with RA progression. It is well accepted that genetic, immunological, and environmental factors contribute to the onset of RA, the cause and detailed pathogenic mechanism of RA are not still well clarified
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