Functional analysis of eosinophil infiltration mechanisms in chronic sinusitis in relation to transcription factor activation

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The overall pathological view of paranasal sinus infection has profoundly changed and evolved in recent decades. A close correlation has been noted between local eosinophil recruitment and the extent of sinus disease through the release of various cytokines and chemokines. In the present study, we have investigated mechanisms of eosinophil infiltration in chronic sinusitis in relation to transcription factor activation1) We examined cytokine expression and the distribution of CD4-positive cell subsets in the sinus mucosa. The patients with low eosinophilia only showed an increase in IFN-γ mRNA expression. In contrast, the other patients showed similar cytokine profiles with high expression levels for GM-CSF, IL-5, eotaxin mRNA CCR4-positive CD4+ cells were also significantly higher in patients with high eosinophilia, leading to decreased CXCR3+/ CCR4+ cell ratio. These findings provide support for the concept of chronic sinusitis as a Th2-mediated disease process2) We examined whether … More the activation of nuclear factor-kappa B (NF-κB) occurred in the sinus mucosa and related the degree of activation to local cytokine gene expression. Both cytoplasmic and nuclear localization of the p50 subunit was observed mainly in the epithelial layer. Significant correlations were observed between the degree of epithelial NF-κB activation and the levels of IL-8, IL-16, and eotaxin mRNA. The activation appears responsible for the recruitment of eosinophils through the initiation of the transcriptional pathway of the related cytokines3) We examined NF-κB activation and concomitant cytokine expression triggered by TNF-α stimulus in cultured sinus epithelial cells. Treatment with TNF-α augmented the degree of NF-κB activation by 2.3 folds. Immunocytochemistry also showed intense nuclear staining with increased staining in the cytoplasm occurred after stimulation. Further, both fluticasone propionate and leukotriene antagonists effectively inhibited the activation in the cultured cells. These results elucidate the molecular mechanisms responsible for the maintenance of constitutive NF-κB activity in sinus mucosa and would provide a direct causal link between the recruitment of eosinophils and persistence of chronic inflammation Less