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

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Abstract
Objective Our previous results suggested that suppression of tumor necrosis factor α (TNFα)–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 TNFα‐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 TNFα alone or with a combination of TNFα 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 TNFα was examined. Results Although TNFα 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 TNFα and cepharanthine. In addition, cepharanthine suppressed the TNFα‐stimulated NF‐κB activity by partly preventing the degradation of IκBα protein in NS‐SV‐AC cells. When NS‐SV‐AC cells were seeded on type IV collagen–coated dishes in the presence of both TNFα 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.