Nitric oxide inhibits IFN regulatory factor 1 and nuclear factor-kappa B pathways in rhinovirus-infected epithelial cells

作者：Koetzler Rommy; Zaheer Raza S; Newton Robert; Proud David^*

来源：Journal of Allergy and Clinical Immunology, 2009, 124(3): 551-557.

DOI：10.1016/j.jaci.2009.04.041

• Human rhinovirus
• asthma
• airway epithelial cells
• CXCL10
• nitric oxide
• IFN regulatory factors
• nuclear factor-kappa B

Background: Nitric oxide (NO) has previously been shown to inhibit human rhinovirus (HRV) replication in airway epithelial cells and to inhibit rhinovirus-induced epithelial cytokine and chemokine production independently of its effects on viral replication by modulating nuclear translocation and binding of transcription factors.
Objective: To define the molecular mechanisms by which NO inhibits HRV-16-induced epithelial production of CXCL10 by affecting nuclear translocation and binding of nuclear factor-kappa B (NF-kappa B) and IFN regulatory factor 1 (IRF-1).
Methods: Cultured human airway epithelial cells were infected with HRV-16 in the absence or presence of a NO donor, or were preincubated with 2 highly selective inhibitors of inhibitor of kappa B kinase (IKK)beta and then infected with HRV-16. Effects on the NF-kappa B and IRF-1 pathways were examined by using electrophoretic mobility shift assays, Western blotting, and real-time RT-PCR.
Results: Nitric oxide directly inhibited the binding of both recombinant NF-kappa B p50 protein and recombinant IRF-1 to their recognition sequences from the CXCL10 promoter. NO also inhibited phosphorylation of the NF-kappa B inhibitor, I kappa B alpha, in HRV-16-infected cells. In addition, both NO and inhibitors of IKK beta inhibited viral induction of IRF-1 mRNA and protein.
Conclusions: Nitric oxide blocks rhinovirus-mediated activation and nuclear translocation of both NF-kappa B and IRF-1. NO also directly inhibits the binding of each of these transcription factors to their respective recognition sites in the CXCL10 promoter. In addition, the ability of HRV- 16 to induce epithelial expression of IRF-1 is dependent, at least in part, on viral activation of NF-kappa B. (J Allergy Clin Immunol 2009;124:551-7.)

• 出版日期2009-9