IL-33/ST2 Regulates Tissue Remodeling Via MAPK and NF-κB Pathways in Nasal Polyp

초록

RATIONALE: Chronic rhinosinusitis is characterized by persistent inflammation and remodeling in the sinonasal mucosa. Fibroblast activation plays an important role in this remodeling process. Interleukin-33 (IL-33), a recently described IL-1 family cytokine via ST2 (IL-33R) receptor, has been implicated in several inflammatory diseases including chronic rhinosinusitis. This study shows that IL-33 activates myofibroblast differentiation and extracellular matrix production via ST2/MAPK/NFκB axis in sinonasal fibroblasts. METHODS: Sinonasal tissues were obtained from healthy, chronic rhinosinusitis without nasal polyposis (CRSsNP), and chronic rhinosinusitis with nasal polyposis (CRSwNP). Nasal fibroblasts were isolated and cultured from inferior turbinate specimens of healthy control cases. Expression levels of α-smooth muscle actin (SMA), fibronectin, IL-33 receptor (ST2), phosphorylated MAP kinases (p38, ERK, and JNK) and activation of NF-κB were determined by reverse transcription-polymerase chain reaction and Western blotting and/or immunofluorescent staining. Type I collagen was defined by qPCR, Western blot analysis, and collagen assay. Contractile activity was measured by a collagen gel contraction assay. Small interfering RNA (siRNA) for ST2 was transfected to down-regulate ST2 expression. RESULTS: IL33 and ST2 expression were upregulated in the nasal polyp mucosa from patients CRSwNPs compared with healthy control and those with CRSsNPs. IL-33 mRNA expression positively correlated with the expression of α-SMA, fibronectin and collagen. IL-33 increased mRNA and protein levels of α-SMA, fibronectin and collagen type 1 and collagen gel contraction in nasal fibroblasts. The inhibition of ST2 by siRNA decreased protein expression of α - SMA, fibronectin and type 1 collagen induced by IL-33. The stimulatory molecular mechanism of IL-33 was involved in ERK, p38, JNK phosphorylation and NF-κB activation in nasal fibroblasts. Their specific inhibitors blocked myofibroblast differentiation and extracellular matrix production in nasal fibroblasts and ex vivo organ culture. CONCLUSION: These findings suggest that IL-33/ST2 regulates tissue remodeling via MAPK and NF-κB pathways through ST2/MAPK/NF-κB signaling pathways in nasal polyp and nasal fibroblasts may play a role for IL-33/ST2-involved CRSwNP formation.