Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression

Abstract

Interleukin 6 (IL-6) was abundant in the tumor microenvironment and played potential roles in tumor progression. In our study, the expression of IL-6 in tumor tissues from 36 gastric cancer (GC) patients was significantly higher than in non-tumor tissues. Moreover, the number of CD163CD206 M2 macrophages that infiltrated in tumor tissues was significantly greater than those infiltrated in non-tumor tissues. The frequencies of M2 macrophages were positively correlated with the IL-6 expression in GC tumors. We also found that IL-6 could induce normal macrophages to differentiate into M2 macrophages with higher IL-10 and TGF-β expression, and lower IL-12 expression, via activating STAT3 phosphorylation. Accordingly, knocking down STAT3 using small interfering RNA decreased the expression of M2 macrophages-related cytokines (IL-10 and TGF-β). Furthermore, supernatants from IL-6-induced M2 macrophages promote GC cell proliferation and migration. Moreover, IL-6 production and CD163CD206 M2 macrophage infiltration in tumors were associated with disease progression and reduced GC patient survival. In conclusion, our data indicate that IL-6 induces M2 macrophage differentiation (IL-10TGF-βIL-12 ) by activating STAT3 phosphorylation, and the IL-6-induced M2 macrophages exert a pro-tumor function by promoting GC cell proliferation and migration.

IL‐6 increases podocyte motility via MLC‐mediated focal adhesion impairment and cytoskeleton disassembly

“…Therefore, on next step, we explored the role of STAT3 signaling in IL‐6 induced MLC phosphorylation as well as the podocyte hypermotility. Not surprisingly, by immunoblotting it is showed that IL‐6 raises the expression of phosphorylated STAT3 and that is in line with studies from other cell lines (Fu et al, ). Then, we used the specific inhibitor stattic to suppress the STAT3 phosphorylation and our data indicated that stattic not only effectively inhibits the phosphorylation of MLC but also obviously attenuates IL‐6 initiated podocyte hypermotility (Figure ).…”

Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism

“…Stat3 signalling in the macrophage is paradoxical because both the pro-inflammatory IL-6 and the anti-inflammatory IL-10 pathways converge on Stat3. Still, Stat3 signalling has been shown to promote macrophage differentiation into the M2/anti-inflammatory phenotype 22,23 and appears to be a mechanism for Metrnl to promote the anti-inflammatory/ regenerative potential of muscle regeneration. Moreover, Metrnl induces macrophage gene expression of both pro-(IL-6) and antiinflammatory (IGF-1/IL-10) genes 24 which could default to the antiinflammatory side of Stat3 signalling; this is observed during dual treatment of IL-10 and IL-6 (ref.…”

Repeated social defeat promotes persistent inflammatory changes in splenic myeloid cells; decreased expression of β-arrestin-2 (ARRB2) and increased expression of interleukin-6 (IL-6)

“…Moreover, previous data show that this cytokine is essential for differentiation of naïve T cells and B cells into effector cells [59][60][61]. In addition, IL-6 production and secretion from splenic myeloid cells may act in an autocrine fashion [53]. Thus, stressinduced splenic upregulation of IL-6 and IL-6 downstream processes may be important for the transition from the acute to persistent immune activation.…”