The product of the human cytomegalovirus (HCMV) gene UL144, expressed at early times postinfection, is located in the UL/b' region of the viral genome and is related to members of the tumor necrosis factor receptor superfamily, but it does not bind tumor necrosis factor superfamily ligands. However, UL144 does activate NF-kappaB, resulting in NF-kappaB-mediated activation of the cellular chemokine CCL22. Consistent with this finding, isolates of HCMV lacking the UL/b' region show no such activation of CCL22. Recently, it has been suggested that activation of NF-kappaB is repressed by the product of the viral gene IE86: IE86 appears to block NF-kappaB binding to DNA but not nuclear translocation of NF-kappaB. Intriguingly, IE86 is detectable throughout an infection with the virus, so how UL144 is able to activate NF-kappaB in the presence of continued IE86 expression is unclear. Here we show that although IE86 does repress the UL144-mediated activation of a synthetic NF-kappaB promoter, it is unable to block UL144-mediated activation of the CCL22 promoter, and this lack of responsiveness to IE86 appears to be regulated by binding of the CREB transcription factor.