Norepinephrine released by the sympathetic nerve terminals regulates the immune system primarily via its stimulation of β2-adrenergic receptor (β2AR), but the underlying molecular mechanisms remain to be elicited. β2AR, a well-studied G protein-coupled receptor (GPCR), is functionally regulated by β-arrestin2, which not only causes receptor desensitization and internalization but also serves as a signaling molecule in GPCR signal transduction. Here we show that β-arrestin2 directly interacts with IκBα (inhibitor of NF-κB, the key molecule in innate and adaptive immunity) and thus prevents the phosphorylation and degradation of IκBα. Consequently, β-arrestin2 effectively modulates activation of NF-κB and expression of NF-κB target genes. Moreover, stimulation of β2AR significantly enhances β-arrestin2-IκBα interaction and greatly promotes β-arrestin2 stabilization of IκBα, indicating that β-arrestin2 mediates a crosstalk between β2AR and NF-κB signaling pathways. Taken together, the current study may present a novel mechanism for regulation of the immune system by the sympathetic nervous system.