Background: IKKε can promote the ability of p52 to transactivate gene expression in a manner requiring p65. Results: p52 is induced by TLR3 activation and regulates Sp1 transcription. Sp1 promotes the transcription of IL-15. Both events require the presence of IKKε and p52. Conclusion: p52 is a target for IKKε in antiviral immunity. Significance: This study reports a role for NFεB2 in the induction of antiviral gene expression. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.