The Kaposi sarcoma–associated herpesvirus (KSHV) induces cellular interleukin 6 expression: role of the KSHV latency-associated nuclear antigen and the AP1 response element

Interleukin (IL) 1β Induction of IL-6 Is Mediated by a Novel Phosphatidylinositol 3-Kinase-dependent AKT/IκB Kinase α Pathway Targeting Activator Protein-1

“…Consistent with this, other investigators have found that the IL-6 promoter AP-1 site is necessary for promoter activation in response to several stimuli including TGF␤ and the Kaposi sarcoma herpes virus (43,62). In our study, mutation of the IL-6 promoter AP-1 site unmasks additional regulation of NFB not observed in the WT IL-6 promoter (Fig.…”

Kaposi's sarcoma-associated herpesvirus encoded vFLIP induces cellular IL-6 expression: the role of the NF-κB and JNK/AP1 pathways

“…Given the known role of the NF-kB and JNK/AP1 pathways in modulating cIL-6 gene expression (Libermann and Baltimore, 1990;Dendorfer et al, 1994), we further postulated that vFLIP activates the cIL-6 promoter and induces cIL-6 protein expression. We recently demonstrated that another KSHV-encoded protein, latencyassociated nuclear antigen (LANA), activates the cIL-6 promoter and induces cIL-6 protein expression (An et al, 2002). Thus, in this report, we also investigated the potential interactions between LANA and vFLIP in the regulation of cIL-6 promoter activity.…”

“…The specificities of the IkB-DA and jun-DN constructs were demonstrated as follows: the IkB-DA completely inhibited vFLIP induction of the pkB-luc plasmid ( Figure 7b, top panel), but had no effect on activation of the JNK/AP1 pathway ( Figure 7b, bottom panel), and the jun-DN inhibited vFLIP activation of the JNK/AP1 pathway ( Figure 7c, top panel) but not the NF-kB pathway ( Figure 7c, bottom panel). We then studied the contribution of the NF-kB and AP1 pathways to activation of the cIL-6 promoter, which was cloned as a 1200 bp region upstream of the transcription start site, as previously described (An et al, 2002). The IkB-DA only partially inhibited vFLIP transactivation of cIL-6 promoter (pIL6-1200/SEAP) ( Figure 7d), and similar results were obtained with the jun-DN (Figure 7e), suggesting that both the NF-kB Total protein was extracted and immunoprecipitated with GST-jun using a kit.…”

“…The pAP1-luc plasmid was cotransfected into R1T cells (a bone marrow stromal cell line; An et al, 2002) or human embryonic kidney 293 cells with an enhanced green fluorescent protein (EGFP)-tagged vFLIP fusion construct (pEGFP-vFLIP) or the EGFP blank vector. Bone marrow stromal cells endogenously express cIL-6 and complement the use of 293 cells, which lack cIL-6 expression.…”

Authors’ Reply to Verdelli et al.: There Is No Knowledge Without Experience

“…The disease was severe in our case, and we had no further therapeutic options available apart from tocilizumab. Although no evidence exists for the safety of tocilizumab therapy in KS, there is a strong theoretical rationale for this treatment [3]. In fact, no relapse of KS was observed, and this is a very positive finding and an interesting solution to the conundrum the patient presented with.…”