Differential control of Toll-like receptor 4–induced interleukin-10 induction in macrophages and B cells reveals a role for p90 ribosomal S6 kinases

Sutavani, Ruhcha V.; Phair, Iain R; Barker, R.J.; McFarlane, Alison; Shpiro, Natalia; Lang, Stuart; Woodland, Andrew; Arthur, J. Simon C.

doi:10.1074/jbc.m117.805424

Cited by 20 publications

(19 citation statements)

References 75 publications

(111 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data indicate that in vivo, MSK1 activity (and, possibly H3S10) downstream of TLR4, is a sort of a "safety fuse", limiting LPS-induced inflammation. Similar mechanism of IL-10 secretion upon TLR4 activation has been shown for macrophages and B-cells, albeit different kinases are mediating these anti-inflammatory responses: macrophages utilize MSK1, whereas B-cells depend on RSK2 [136].…”

Section: Iκb Kinase α (Ikkα Chuk) and Inflammatory Pathway-induced Ksupporting

confidence: 52%

Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy

Komar

Juszczyński

2020

Clin Epigenet

View full text Add to dashboard Cite

Background With the discovery that more than half of human cancers harbor mutations in chromatin proteins, deregulation of epigenetic mechanisms has been recognized a hallmark of malignant transformation. Post-translational modifications (PTMs) of histone proteins, as main components of epigenetic regulatory machinery, are also broadly accepted as therapeutic target. Current “epigenetic” therapies target predominantly writers, erasers and readers of histone acetylation and (to a lesser extent) methylation, leaving other types of PTMs largely unexplored. One of them is the phosphorylation of serine 10 on histone H3 (H3S10ph). Main body H3S10ph is emerging as an important player in the initiation and propagation of cancer, as it facilitates cellular malignant transformation and participates in fundamental cellular functions. In normal cells this histone mark dictates the hierarchy of additional histone modifications involved in the formation of protein binding scaffolds, transcriptional regulation, blocking repressive epigenetic information and shielding gene regions from heterochromatin spreading. During cell division, this mark is essential for chromosome condensation and segregation. It is also involved in the function of specific DNA–RNA hybrids, called R-loops, which modulate transcription and facilitate chromosomal instability. Increase in H3S10ph is observed in numerous cancer types and its abundance has been associated with inferior prognosis. Many H3S10-kinases, including MSK1/2, PIM1, CDK8 and AURORA kinases, have been long considered targets in cancer therapy. However, since these proteins also participate in other critical processes, including signal transduction, apoptotic signaling, metabolic fitness and transcription, their chromatin functions are often neglected. Conclusions H3S10ph and enzymes responsible for deposition of this histone modification are important for chromatin activity and oncogenesis. Epigenetic-drugs targeting this axis of modifications, potentially in combination with conventional or targeted therapy, provide a promising angle in search for knowledge-driven therapeutic strategies in oncology.

show abstract

Section: Iκb Kinase α (Ikkα Chuk) and Inflammatory Pathway-induced Ksupporting

confidence: 52%

Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy

Komar

Juszczyński

2020

Clin Epigenet

View full text Add to dashboard Cite

show abstract

“…Nevertheless, Hildebrand et al indicated that TLR‐4 mediated STAT3 activation remodels myeloid cells towards an immunosuppressive phenotype 27 . Moreover, in the concept of lymphoid lineage, recent findings suggested that signalling through TLR2 and TLR4 directly down‐regulates T‐cell effector function and promotes IL‐10 production by B cells that proposed to be dependent on the STAT3 activation 21,28 . The present obtained results showed that tropisetron strongly up‐regulates LPS‐stimulated TLR2 and TLR4 gene expression.…”

Section: Discussionsupporting

confidence: 56%

Tropisetron balances immune responses via TLR2, TLR4 and JAK2/STAT3 signalling pathway in LPS‐stimulated PBMCs

Karimollah

Hemmatpur

Hosseini

et al. 2021

Basic Clin Pharma Tox

View full text Add to dashboard Cite

Numerous documents have been stated that tropisetron, an antagonist of the 5‐HT3 receptor and α7nAChR agonist, modulates immune responses. However, the mechanistic basis for this aspect of tropisetron action is largely unknown. Here, the immuno‐modulatory effects of tropisetron are investigated, focusing on the possible molecular targets and the mechanisms. Aside from the well‐characterized role in immune signalling, JAK2/STAT3, TLR2 and TLR4 are signal transducers linked to both immuno‐modulatory actions of acetylcholine and serotonin. Therefore, we evaluated their involvement in the immunoregulatory effects of tropisetron. To test the hypothesis, we assessed the expression of pro‐/anti‐inflammatory cytokines including TNF‐α, IL‐1β, IL‐17 and IL‐10 following tropisetron treatment in lipopolysaccharide (LPS)‐stimulated peripheral blood mononuclear cells (PBMCs) derived from healthy subjects. Tropisetron up‐regulates the transcription of TLR2, TLR4, JAK2 and STAT3 genes. Tropisetron also increases the expression of target pro‐inflammatory cytokines, although considerably suppresses the pro‐inflammatory cytokines (IL‐1β, IL‐17 and TNF‐α) levels in media. Tropisetron notably promotes both IL‐10 gene expression and secretion. These findings confirm the antiphlogistic properties of tropisetron. The present data also shed light on a new aspect of tropisetron immune‐modulatory action that engaged TLR2, TLR4 and JAK2/STAT3 signalling cascades.

show abstract

“…ERK1/2 signaling has been implicated in IL-10 expression in multiple cell types (Saraiva & O’Garra, 2010; Iyer & Cheng, 2012; Kubo & Motomura, 2012; Sanin et al., 2015; Garaud et al., 2018; Zhang & Kuchroo, 2019). Of particular interest are data revealing that in both human and mouse B-cells, TLR-mediated ERK1/2 activation is critical to induce IL-10 production, suggesting that the expression of MEK1DD may directly upregulate IL-10 transcription in splenic B-cells (Liu et al., 2014; Sutavani et al., 2018). Taken together, these data suggest that ERK1/2 signaling promotes splenic B-cell activation and the expansion of CD5 + CD1d hi and CD138 + B-cell subsets, and may drive IL-10 expression in one or both of these populations.…”

Section: Discussionmentioning

confidence: 99%

CnpPromoter-Driven Sustained ERK1/2 Activation Increases B-Cell Activation and Suppresses Experimental Autoimmune Encephalomyelitis

et al. 2020

View full text Add to dashboard Cite

The ERK1/2 signaling pathway promotes myelin wrapping during development and remyelination, and sustained ERK1/2 activation in the oligodendrocyte (OL) lineage results in hypermyelination of the CNS. We therefore hypothesized that increased ERK1/2 signaling in the OL lineage would 1) protect against immune-mediated demyelination due to increased baseline myelin thickness and/or 2) promote enhanced remyelination and thus functional recovery after experimental autoimmune encephalomyelitis (EAE) induction. Cnp-Cre;Mek1DD-eGFP/+ mice that express a constitutively active form of MEK1 (the upstream activator of ERK1/2) in the OL lineage, exhibited a significant decrease in EAE clinical severity compared to controls. However, experiments using tamoxifen-inducible Plp-CreERT;Mek1DD-eGFP/+ or Pdgfrα-CreERT;Mek1DD-eGFP mice revealed this was not solely due to a protective or reparative effect resulting from MEK1DD expression specifically in the OL lineage. Because EAE is an immune-mediated disease, we examined Cnp-Cre; Mek1DD-eGFP/+ splenic immune cells for recombination. Surprisingly, GFP+ recombined CD19+ B-cells, CD11b+ monocytes, and CD3+ T-cells were noted when Cre expression was driven by the Cnp promoter. While ERK1/2 signaling in monocytes and T-cells is associated with proinflammatory activation, fewer studies have examined ERK1/2 signaling in B-cell populations. After in vitro stimulation, MEK1DD-expressing B-cells exhibited a 3-fold increase in CD138+ plasmablasts and a 5-fold increase in CD5+CD1dhi B-cells compared to controls. Stimulated MEK1DD-expressing B-cells also exhibited an upregulation of IL-10, known to suppress the initiation of EAE when produced by CD5+CD1dhi regulatory B-cells. Taken together, our data support the conclusion that sustained ERK1/2 activation in B-cells suppresses immune-mediated demyelination via increasing activation of regulatory B10 cells.

show abstract

Differential control of Toll-like receptor 4–induced interleukin-10 induction in macrophages and B cells reveals a role for p90 ribosomal S6 kinases

Cited by 20 publications

References 75 publications

Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy

Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy

Tropisetron balances immune responses via TLR2, TLR4 and JAK2/STAT3 signalling pathway in LPS‐stimulated PBMCs

CnpPromoter-Driven Sustained ERK1/2 Activation Increases B-Cell Activation and Suppresses Experimental Autoimmune Encephalomyelitis

Contact Info

Product

Resources

About