TNFαMediated IL-6 Secretion Is Regulated by JAK/STAT Pathway but Not by MEK Phosphorylation and AKT Phosphorylation in U266 Multiple Myeloma Cells

Abstract

IL-6 and TNFα were significantly increased in the bone marrow aspirate samples of patients with active multiple myeloma (MM) compared to those of normal controls. Furthermore, MM patients with advanced aggressive disease had significantly higher levels of IL-6 and TNFα than those with MM in plateau phase. TNFα increased interleukin-6 (IL-6) production from MM cells. However, the detailed mechanisms involved in signaling pathways by which TNFα promotes IL-6 secretion from MM cells are largely unknown. In our study, we found that TNFα treatments induce MEK and AKT phosphorylation. TNFα-stimulated IL-6 production was abolished by inhibition of JAK2 and IKKβ or by small interfering RNA (siRNA) targeting TNF receptors (TNFR) but not by MEK, p38, and PI3K inhibitors. Also, TNFα increased phosphorylation of STAT3 (ser727) including c-Myc and cyclin D1. Three different types of JAK inhibitors decreased the activation of the previously mentioned pathways. In conclusion, blockage of JAK/STAT-mediated NF-κB activation was highly effective in controlling the growth of MM cells and, consequently, an inhibitor of TNFα-mediated IL-6 secretion would be a potential new therapeutic agent for patients with multiple myeloma.

Abnormal repression of SHP-1, SHP-2 and SOCS-1 transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma

“…Thus, we consolidate the idea that the inactivation of genes regulating the JAK/STAT3 pathway can support tumor expansion through the repression of JAK/STAT signaling. In addition to its anti-apoptotic effect, the JAK/STAT pathway can also enhance IL-6 production [39, 40]. This can lead to the establishment of a positive feedback loop that amplifies the IL-6R/JAK/STAT3 pathway.…”

The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice

“…It is recently accepted that Rac1 plays an important role in modulating PI3K/Akt/IKK/NF-κB signalings [41]. Meanwhile, evidence has been published to show that JAK/STAT pathway is associated with the regulation of Akt/NF-κB cascade and MAPKs [42,43].…”

Functional analysis of the fractalkine gene promoter in human aortic smooth muscle cells exposed to proinflammatory conditions

“…Thus, we found previously that resistin induces Fk expression in human SMCs that is dependent on not only NF-jB and JAK-STAT, but also AP-1 [3]. Moreover, TNF-a and IFN-c use a similar mechanism to induce Fk expression in endothelial cells and osteoblasts [24,41]. Thus, the elevated level of Fk induced by TNF-a in human umbilical vein endothelial cells was significantly reduced by a JAK3 inhibitor (JANEX-1), which suppressed STAT3 phosphorylation and NF-jB activation [41].…”

“…Moreover, TNF-a and IFN-c use a similar mechanism to induce Fk expression in endothelial cells and osteoblasts [24,41]. Thus, the elevated level of Fk induced by TNF-a in human umbilical vein endothelial cells was significantly reduced by a JAK3 inhibitor (JANEX-1), which suppressed STAT3 phosphorylation and NF-jB activation [41]. Similarly, in other studies, Fk expression was increased by TNF-a and IFN-c in osteoblasts through activation of NF-jB and STAT-1 [24].…”