Effect of FK506 and Cyclosporin A on I(kappa)B(alpha) Degradation and IKK Pathway in Bronchial Epithelial Cells, Monocytes, Lymphocytes and Alveolar Macrophages / 결핵

ABSTRACT

BACKGROUND: Cyclosporin A(CsA) and tacrolimus(FK506) have been widely used as immunosuppressants. The effects of CsA, or FK506, on the IkappaB/NF-kappaB pathway have been shown to vary according to the cell type. However, their effects on the IkappaB/NF-kappaB pathway have not been reported in bronchial epithelial cells. In this study, the effects of CsA and FK506 on the IkappaB/NF-kappaB pathway in bronchial epithelial cells, monocytes, lymphocytes and alveolar macrophages were evaluated. The relationship between their effects on the IkappaB/NF-kappaB pathway and IkappaB kinase(IKK) activity was also investigated. METHODS: BEAS-2B and A549 cells, pulmonary alveolar macrophages, peripheral blood monocytes and lymphocytes were used. The cells were pre-treated with CsA, or FK506, for various time periods, followed by stimulation with TNF-alpha, LPS or IL-1beta. The I(kappa)B(alpha) expressions were assayed by Western blot analyses. The IKK activity was evaluated by an in vitro immune complex kinase assay, using GST-I(kappa)B(alpha) as the substrate. RESULTS: Neither CsA nor FK506 affected the level of I(kappa)B(alpha) expression in any of the cell types used in this study. CsA pre-treatment inhibited the TNFalpha-induced I(kappa)B(alpha) degradation in bronchial epithelial cells. In contrast, the TNFalpha-induced I(kappa)B(alpha) degradation was not affected by FK506 pre-treatment. However, FK506 suppressed the cytokine-induced I(kappa)B(alpha) degradation in the pulmonary alveolar macrophages, peripheral blood monocytes and lymphocytes. The inhibitory effect of CsA, or FK506, on I(kappa)B(alpha) degradation was not related to IKK. CONCLUSIONS: CsA and FK506 suppressed the I(kappa)B(alpha) degradation in bronchial epithelial cells, mono. cytes, lymphocytes and alveolar macrophages, so this may not be mediated through IKK.