Tumor Necrosis Factor α up-regulates the Expression of beta2 Adrenergic Receptor via NF-κB-dependent Pathway in Osteoblasts
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Tumor necrosis factor alpha (TNFα) is a multifunctional inflammatory cytokine that regulates various cellular and biological processes. Increased levels of TNFα have been implicated in a number of human diseases including diabetes and arthritis. Sympathetic nervous system stimulation via the beta2-adrenergic receptor (β2AR) in osteoblasts suppresses osteogenic activity. We previously reported that TNFα upregulates β2AR expression in murine osteoblastic cells and that this modulation is associated with TNFα inhibition of osteoblast differentiation. In our present study, we explored whether TNFα induces β2AR expression in human osteoblasts and then identified the downstream signaling pathway. Our results indicated that β2AR expression was increased in Saos-2 and C2C12 cells by TNFα treatment, and that this increase was blocked by the inhibition of NF-κB activation. Chromatin immunoprecipitation and luciferase reporter assay results indicated that NF-κB directly binds to its cognate elements on the β2AR promoter and thereby stimulates β2AR expression. These findings suggest that the activation of TNFα signaling in osteoblastic cells leads to an upregulation of β2AR and also that TNFα induces β2AR expression in an NF-κB-dependent manner.
Abstract
Tumor necrosis factor alpha (TNFα) is a multifunctional inflammatory cytokine that regulates various cellular and biological processes. Increased levels of TNFα have been implicated in a number of human diseases including diabetes and arthritis. Sympathetic nervous system stimulation via the beta2-adrenergic receptor (β2AR) in osteoblasts suppresses osteogenic activity. We previously reported that TNFα upregulates β2AR expression in murine osteoblastic cells and that this modulation is associated with TNFα inhibition of osteoblast differentiation. In our present study, we explored whether TNFα induces β2AR expression in human osteoblasts and then identified the downstream signaling pathway. Our results indicated that β2AR expression was increased in Saos-2 and C2C12 cells by TNFα treatment, and that this increase was blocked by the inhibition of NF-κB activation. Chromatin immunoprecipitation and luciferase reporter assay results indicated that NF-κB directly binds to its cognate elements on the β2AR promoter and thereby stimulates β2AR expression. These findings suggest that the activation of TNFα signaling in osteoblastic cells leads to an upregulation of β2AR and also that TNFα induces β2AR expression in an NF-κB-dependent manner.
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