Cytomegalovirus Induction of Interleukin‐6 in Lung Fibroblasts Occurs Independently of Active Infection and Involves a G Protein and the Transcription Factor, NF‐𝛋B

Abstract

Cytomegalovirus (CMV) infection induces the proinflammatory cytokine, interleukin (IL)-6, which may contribute to the pathology of the infection. In vitro CMV induction of IL-6 by human lung fibroblasts was studied. The quantity of cytokine in culture supernatants was maximal 20 h after infection and decreased thereafter. Transcription of the IL-6 gene and IL-6 protein expression were equally stimulated by infectious and UV-inactivated virus (CMV-UV). CMV-UV-stimulated IL-6 was inhibited by pyrrolidinedithiocarbamate (an inhibitor of the transcription factor, NF-kappaB) and by pertussis toxin (suggesting the involvement of a G protein) and occurred in the absence of CMV immediate-early antigen transcription. Neutralizing antibodies to IL-1beta or tumor necrosis factor-alpha did not affect CMV-UV-induced IL-6, but expression was inhibited by antibody to the CMV attachment glycoprotein. IL-6 production by fibroblasts occurs independently from productive infection but has characteristics that suggest a ligand receptor-mediated pathway. This function may be important in pathology or disease resolution.

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

“…84 Moreover, HCMV infection activates NF-kB signaling in fibroblasts and monocytes, 85e88 and NF-kB regulates GADD45a and Bcl-x L . Both NF-kB and IE proteins stimulate IL-6 production, 83,89,90 and an IL-6erelated pathway up-regulates GADD45b in herpes simplex virus-1einfected corneal epithelial cells. 91 …”

Corneal IL-8 Expression Following Adenovirus Infection Is Mediated by c-Src Activation in Human Corneal Fibroblasts

“…The ability of UV-inactivated viruses to induce cytokines has previously been shown in a variety of systems (50,51), indicating that virus replication is not always necessary to initiate a host response. The absence of one of the most abundantly expressed early adenoviral gene transcripts, E1A-13S, at a time when IL-8 message is already up-regulated, and the ability of HCF to secrete IL-8 when infected with UV-inactivated Ad19 indicate that Ad19 replication is not essential to early IL-8 production.…”

RICK Activates a NF-κB-dependent Anti-human Cytomegalovirus Response

“…HCMV, like other herpes viruses, encodes several G-proteincoupled receptors, and it has been demonstrated that one, the US28 gene product, can activate NF-B (35,36), possibly by means of activation of the phosphatidylinositol 3-kinase/Akt pathway (37). Inhibition of this function by pertussis toxin suggests a role for G-protein activation (45). Thus, one interpretation of these results is that NF-B activation is a positive factor for HCMV replication, and that inhibiting NF-B activation could be a useful strategy to block the virus.…”