Suppression of tumor necrosis factor α–induced matrix metalloproteinase 9 production in human salivary gland acinar cells by cepharanthine occurs via down‐regulation of nuclear factor κB: A possible therapeutic agent for preventing the destruction of the acinar structure in the salivary glands of Sjögren's syndrome patients

Abstract

Objective. Our previous results suggested that suppression of tumor necrosis factor ␣ (TNF␣)-induced matrix metalloproteinase 9 (MMP-9) could prevent the destruction of acinar tissue in the salivary glands of patients with Sjögren's syndrome (SS). The present study was undertaken to investigate the effect of cepharanthine on the suppression of TNF␣-induced MMP-9 production in NS-SV-AC, an SV40-immortalized normal human acinar cell clone.Methods. After pretreatment with or without cepharanthine, NS-SV-AC cells were treated with TNF␣ alone or with a combination of TNF␣ and cepharanthine. The expression of MMP-9 was then examined at the protein and messenger RNA levels. In addition, the effect of cepharanthine on the morphogenetic behavior of NS-SV-AC cells cultured on type IV collagen-coated dishes in the presence of TNF␣ was examined.Results. Although TNF␣ induced the production of MMP-9 in NS-SV-AC cells, this production was greatly suppressed when cells were pretreated with cepharanthine, followed by treatment with both TNF␣ and cepharanthine. In addition, cepharanthine suppressed the TNF␣-stimulated NF-B activity by partly preventing the degradation of IB␣ protein in NS-SV-AC cells. When NS-SV-AC cells were seeded on type IV collagen-coated dishes in the presence of both TNF␣ and plasmin, type IV collagen interaction with the cells was lost and the cells entered apoptosis. However, pretreatment with cepharanthine restored the aberrant in vitro morphogenesis of the NS-SV-AC cells.Conclusion. These results may indicate a molecular mechanism by which cepharanthine is able to protect against the destruction of the acinar structure in salivary glands from patients with SS.

Lack of efficacy of etanercept in Sjogren syndrome correlates with failed suppression of tumour necrosis factor and systemic immune activation

“…TNFα has been identified systemically and locally in the exocrine glands of patients with SS,22 23 and contributes to the establishment and progression of exocrine gland pathology in animal models 4 24. Furthermore, the use of TNF inhibitors has led to successful treatment of many autoimmune conditions 8.…”

Inhibition of the STAT3 signaling pathway is involved in the antitumor activity of cepharanthine in SaOS2 cells

“…The pharmacological activities of CEP include the reversal of multidrug resistance [5][6][7] , antitumor activity [8][9][10] and inhibiting the production of inflammatory mediators [11][12][13][14] .…”

Inhibitory effect of cepharanthine on dendritic cell activation and function

“…NF-κB is known to play a key role in upregulating costimulatory molecules and MHC class I, and induction of inflammatory cytokines [3]. Although CEP exerts its antitumor activity through the inhibition of NF-κB, its molecular mechanism in inhibiting NF-κB has not been fully elucidated yet [16][17][18]. CEP did not affect the degradation of IκB, an inhibitory molecule of NF-κB (data not shown).…”