HCMV-encoded UL128 enhances TNF-α and IL-6 expression and promotes PBMC proliferation through the MAPK/ERK pathway in vitro.

Cytomegalovirus (CMV) infection enhances expression of several cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-8, to the benefit of virus replication and dissemination. However, the stimulus for certain cytokine production remains unclear. CMV encodes a series of proteins that alter and/or mimic functions of leukocyte migration, activation, and cytokine responses. Our study revealed that human CMV (HCMV)-encoded UL128 protein, which contains signal peptides and has similar amino acid sequences to the CC chemokine, recruits monocytes as human β chemokine (microphage inflammatory protein 1α). Using RNA interference technology, we constructed an HCMV (UL128⁺/UL128⁻)-infected tissue cell (MRC-5) and peripheral blood mononuclear cell (PBMC) co-culture system. We measured 6 cytokine levels (IL-2, IL-4, IL-6, IL-10, TNF-α, and interferon-γ [IFN-γ]) in the supernatant, and found significantly elevated IL-6 and elevated TNF-α levels in the HCMV UL128⁺-infected group. Conversely, we observed decreased levels in the UL128-knockout supernatant. PBMCs presented with UL128 (50 ng/mL) demonstrated better cell viability than the UL128-absent group. Finally, the MAPK/ERK pathway was found to be involved in UL128 induction of cell proliferation. Selective induction of cytokine expression indicates that HCMV-encoded UL128 is a potent inducer of several inflammatory mediators.