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Background: This study aimed to explore the responses to the interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) complex in peritumoral endothelial cells (PECs) and tumor endothelial cells (TECs), as well as determine the signaling pathways in the angiogenesis of hepatocellular carcinoma (HCC).Methods: The expression of IL-6, IL-6R, gp130, CD68, HIF-1α, and microvessel density (MVD) were assessed with an orthotopic xenograft model in nude mice. ECs were incubated under hypoxic conditions to detect IL-6 and gp130. The proliferation of PECs and TECs in the presence of IL-6 and sIL-6R, as well as the expression of gp130, JAK2/STAT3, PI3K/AKT in endothelial cells were measured.Results: Peritumoral IL-6, IL-6R, gp130, CD68, and HIF-1α expression, as well as MVD, gradually increased during tumor growth. Hypoxia could directly induce IL-6 expression, but not gp130 in PECs. The co-culture of IL-6/sIL-6R induced much higher PEC proliferation and gp130 expression, as well as the elevated phosphorylation of JAK2 and STAT3, however not the phosphorylation of PI3K and AKT.Conclusions: PECs exhibited higher proliferation in response to IL-6/sIL-6R co-treatment compared with TECs in HCC via the up-regulation of gp130 /JAK2/STAT3. PEC and its associated peritumoral angiogenesis microenvironment may be a potential novel target for anti-angiogenic treatment. [ABSTRACT FROM AUTHOR]

T cell activation causes the translocation of NF-kB dimers from the cytoplasm into the nucleus where NF-kB regulates inflammatory and immune response genes. Cbl-b is a negative regulator of T cell activation. However, the correlation between NF-kB activity and Cbl-b expression remains unclear. We showed that IKBαΔN-Tg T cells exhibited less NF-kB activity but higher levels of Cbl-b when compared with wild-type T cells. Furthermore, ursolic acid suppressed NF-kB activation and inhibited the downregulation of Cbl-b in wild-type T cells. NF-KBp65 specifically bound to an 11-bp NF-kB consensus sequence (gcaggaagtcc) in the Cbl-b promoter. Binding of NF-kB to this sequence suppressed Cbl-b transcription, thereby resulting in the negative regulation of Cbl-b expression. In addition, Cbl-b knockout led to the loss of cardiac allograft tolerance in IKBαΔN-Tg mice. These results indicated that NF-kB downregulated Cbl-b by binding and suppressing Cbl-b promoter in T cell activation. Our findings provide a novel role for NF-kB signaling in T cell activation. [ABSTRACT FROM AUTHOR]