Modulation of host immune responses is a common strategy for promoting virus persistence and avoiding clearance. Human cytomegalovirus (HCMV) is known to encode numerous immunomodulatory genes, including a homolog of the cytokine human interleukin-10 (hIL-10). While having limited sequence homology to hIL-10, cytomegalovirus IL-10 (cmvIL-10) shares many functional characteristics with the human cytokine and acts as a potent suppressor of the inflammatory immune response. The mechanism by which hIL-10 inhibits inflammatory cytokines involves a transcriptional block via inhibition of nuclear factor-κB (NF-κB) activity. To determine whether cmvIL-10 employs the same mechanism to inhibit cytokine production, the effect of cmvIL-10 on NF-κB signaling in monocytes was investigated. The results demonstrate that cmvIL-10 does inhibit NF-κB activation, as evidenced by reduced degradation of the NF-κB inhibitor IκB-α, and decreased transcription of the NF-κB–responsive genes tumor necrosis factor-α (TNF-α) and IL-1β. These studies confirm that cmvIL-10 mediates cytokine suppression by blocking NF-κB transcriptional activity in human monocytes.

Human cytomegalovirus (CMV) has evolved numerous strategies for evading host immune defenses, including piracy of cellular cytokines. A viral homolog of interleukin-10, designated cmvIL-10, binds to the cellular IL-10 receptor and effects potent immune suppression. The signaling pathways employed by cmvIL-10 were investigated, and the classic IL-10R/JAK1/Stat3 pathway was found to be activated in monocytes. However, inhibition of JAK1 had little effect on cmvIL-10-mediated suppression of tumor necrosis factor alpha (TNF-α) production. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway had a more significant impact on TNF-α levels but did not completely relieve the immune suppression, demonstrating that cmvIL-10 stimulates multiple signaling pathways to modulate cell function.

Cancer is the result of unregulated cell growth that leads to tumor formation, and in many cases, metastases. Although there are several risk factors associated with cancer, one area that remains poorly understood is the impact of infectious disease. Human cytomegalovirus (HCMV) is a member of the herpesvirus family that is highly prevalent in the population. HCMV usually causes clinical disease only in immune compromised individuals, but recent evidence suggests that HCMV may be strongly associated with some forms of cancer, particularly glioblastoma and breast cancer. We investigated the possibility that cmvIL-10, a viral cytokine with homology to human IL-10 that is secreted from infected cells, could act in a paracrine manner to alter the tumor microenvironment, induce cell signaling, and increase the invasive potential of cancer cells. We found that human MDA-MB-231 breast cancer cells express the IL-10 receptor and that exposure to cmvIL-10 results in activation of Stat3, a transcription factor strongly associated with enhanced metastatic potential and chemo-resistance. In addition, cmvIL-10 stimulated an increase in DNA synthesis and cell proliferation, protected MDA-MB-231 cells from etoposide-induced apoptosis, and also greatly enhanced chemotaxis toward epidermal growth factor (EGF). These results suggest a significant and wide-ranging role for cmvIL-10 in the progression of breast cancer and could have broad implications for the diagnosis and treatment of cancer in HCMV-positive patients.