Cytomegalovirus immediate early genes upregulate interleukin-6 gene expression

Background: The immediate early genes (IE) of human cytomegalovirus (CMV) can be expressed in monocytic cells and are known to regulate viral and cellular genes, Interleukin-6 (IL-6) plays a central role in numerous inflammatory and immune processes, Interleukin-6 levels are increased in lung transplant patients clinically diagnosed with CMV pneumonitis, The regulation of IL-6 is dependent on various stimuli that include lipopolysaccharide (LPS), viruses, and other cytokines, These studies examined the ability of CMV IE gene products to modulate IL-6 production. Methods: THP-1 cells, a monocytic cell line, were transfected with the CMV IE genes, Interleukin-6 protein and IL-6 mRNA were measured in control and CMV immediate early transfected cells, Cotransfection of CMV IE genes and IL-6 chloramphenicol acetyl transferase (CAT) or IL-6 luciferase constructs were used to study IL-6 promoter activity. Results: Interleukin-6 protein and mRNA production were significantly increased in cells transfected with the CMV IE genes and stimulated with LPS compared to LPS-stimulated control cells, Cytomegalovirus IE gene products significantly enhanced LPS stimulation of IL-6 promoter activity in both IL-6 CAT and IL-6 luciferase assays, A deletion construct that contains a NF-kappa B site but is missing the multiple response region demonstrated a continued increase in IL-6 luciferase activity in LPS-stimulated CMV transfected cells. Conclusion: Cytomegalovirus immediate early gene products significantly enhanced expression of IL-6 in LPS-stimulated cells, The increase in IL-6 luciferase activity occurs in the absence of the multiple response region, the area of the IL-6 promoter responsive to IL-1, TNF alpha, cyclic amp, and phorbol 12-myristate 13-acetate, The ability of CMV IE gene products to enhance IL-6 production may play an important role in immune inflammatory states associated with CMV infection.