Proteasome inhibitors, used in cancer treatment for their pro-apoptotic effects, have anti-inflammatory and anti-fibrotic effects on animal models of various inflammatory and fibrotic diseases. Their effects in cells from patients affected by either inflammatory or fibrotic diseases have been poorly investigated. Nasal polyposis is a chronic inflammatory disease of the sinus mucosa characterized by tissue inflammation and remodeling. We tested the hypothesis that proteasome inhibition of nasal polyp fibroblasts might reduce their proliferation and their inflammatory and fibrotic response. Accordingly, we investigated the effect of the proteasome inhibitor MG262 on cell viability and proliferation, and on the production of collagen and inflammatory cytokines, in nasal polyp and nasal mucosa fibroblasts obtained from surgery specimens. MG262 reduced the viability of nasal mucosa and polyp fibroblasts dose- and time-dependently, with marked effects after 48 h of treatment. The proteasome inhibitor bortezomib provoked a similar effect. MG262-induced cell death involved loss of mitochondrial membrane potential, caspase-3 and poly (ADP-ribose) polymerase activation, induction of c-Jun phosphorylation, and mitogen-activated protein kinase phosphatase-1 expression. Low concentrations of MG262 provoked growth arrest, inhibited DNA replication and retinoblastoma phosphorylation, and increased expression of the cell cycle inhibitors p21 and p27. MG262 dose-dependently inhibited basal and TGF-β-induced collagen mRNA expression and IL-1β-induced production of IL-6, IL-8, MCP-1, RANTES and GM-CSF in both fibroblast types. MG262 inhibited IL-1β/TNF-α-induced activation of NF-κB. We conclude that non-cytotoxic treatment with MG262 reduces the proliferative, fibrotic, and inflammatory response of nasal fibroblasts, whereas high MG262 concentrations induce apoptosis.
- Received December 2, 2011.
- Revision received July 3, 2012.
- Accepted July 3, 2012.
- The American Society for Pharmacology and Experimental Therapeutics