IL6 inhibition of inflammatory S100A8/9 proteins is NF‐κB mediated in essential thrombocythemia

Abstract

This study has been performed to determine the mechanism of activation of the myeloid related S100A proteins by inflammatory cytokines in myeloproliferative neoplasm (MPN). Besides microarray analysis of MPN-derived CD34 + cells, we analysed the proinflammatory IL6 and anti-inflammatory IL10 dependence of NF-κB, PI3K-AKT, and JAK-STAT signalling during induction of S100A proteins in mononuclear cells of MPN, by immunoblotting and flow cytometry. We observed the reduced gene expression linked to NF-κB and inflammation signalling in MPN-derived CD34 + cells. Both IL6 and IL10 reduced S100A8 and 100A9 protein levels mediated via NF-κB and PI3K signalling, respectively, in mononuclear cells of essential thrombocythemia (ET). We also determined the increased percentage of S100A8 and S100A9 positive granulocytes in ET and primary myelofibrosis, upgraded by the JAK2V617F mutant allele burden. S100A8/9 heterodimer induced JAK1/2-dependent mitotic arrest of the ET-derived granulocytes.Significance of the study: We demonstrated that inflammation reduced the myeloid related S100A8/9 proteins by negative feedback mechanism in ET. S100A8/9 can be a diagnostic marker of inflammation in MPN, supported by the concomitant NF-κB and JAK1/2 signalling inhibition in regulation of myeloproliferation and therapy of MPN. K E Y W O R D SG2/M phase, interleukin 10, interleukin 6, myeloproliferative neoplasm, NF-κB signalling, S100A8/9

KLHDC7B-DT aggravates pancreatic ductal adenocarcinoma development via inducing cross-talk between cancer cells and macrophages

“…PTEN-PI3K-AKT signaling and STAT3 signaling have been revealed to be involved in the macrophages M2 polarization [38][39][40]. IL-6 is also frequently reported to activate AKT and STAT3 [41,42]. Therefore, we further investigated whether KLHDC7B-DT modulated macrophages M2 polarization using the in vitro indirect coculture system (Figure 6A).…”

Platelet proteo-transcriptomic profiling validates mediators of thrombosis and proteostasis in patients with myeloproliferative neoplasms

“…ET: 2 (increased) The S100 family of proteins is a major player in hematopoietic proliferation and recent work has identified proinflammatory/profibrotic roles for S100A6, S100A8, S100A9 in bone marrow, granulocytes, and plasma in MPN [80][81][82][83][84][85] We show evidence of dysregulated protein degradation pathways with upregulation of PSMD11 along with differential expression of lysosomal proteins (SORT1 and ATP6V) and other proteasomal subunits. This reflects the work of other groups who have shown that protein qualitycontrol pathways may be important in the pathogenesis of MPN and other prothrombotic diseases and represent novel therapeutic targets [101][102][103] .…”

JAK signaling was involved in the pathogenesis of Polymyalgia Rheumatica

“…2B). They can activate the JAK-signal transducer and activator of transcription (STAT) pathway [8][9][10][11][12][13][14][15][16][17][18]. They were also related to the function of monocytes, T cells, and neutrophils.…”

“…S100A8 and S100A12 are calcium-binding, zinc-binding proteins, and inflammatory mediators. S100A8 can induce the JAK1/2-dependent signaling [13]. S100A12 was induced by IL-6 via JAK signaling [14].…”