TLR4 and RAGE conversely mediate pro-inflammatory S100A8/9-mediated inhibition of proliferation-linked signaling in myeloproliferative neoplasms

Kovačić, Marijana; Ajtić, Olivera Mitrović; Beleslin-Čokić, Bojana B.; Djikić, Dragoslava; Subotički, Tijana; Diklić, Miloš; Leković, Danijela; Gotić, Mirjana; Mossuz, Pascal; Čokić, Vladan P.

doi:10.1007/s13402-018-0392-6

Cited by 37 publications

(32 citation statements)

References 27 publications

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“…We already demonstrated that S100A8 and S100A9 protein levels were increased in granulocytes and plasma of patients with MPN, along with inflammation markers . Moreover, S100A8/9 inhibition of PI3K/AKT and ERK1/2 signalling pathways was conversely regulated by RAGE/TLR4 receptors in MPN . In this study, we hypothesized that inflammatory induction of the myeloid‐related S100 proteins is NF‐κB mediated in MPN.…”

Section: Introductionmentioning

confidence: 76%

“…In accordance with the previous reports, S100 proteins mediated inflammatory response and activated NF‐κB signalling. We already demonstrated that S100A8 and S100A9 protein levels were increased in granulocytes and plasma of patients with MPN, along with inflammation markers . Moreover, S100A8/9 inhibition of PI3K/AKT and ERK1/2 signalling pathways was conversely regulated by RAGE/TLR4 receptors in MPN .…”

Section: Introductionmentioning

confidence: 77%

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

Diklić

Ajtić

Subotički

et al. 2019

Cell Biochemistry & Function

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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

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Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 77%

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

Diklić

Ajtić

Subotički

et al. 2019

Cell Biochemistry & Function

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“…S100A12 binds to and activates the RAGE receptor, which can lead to increased NF-κB activation, proinflammatory signaling, and the initiation of inflammation responses [9,10,28,30,32,40,43,85]. S100A12 also binds to the TLR-4 receptor to promote proin-flammatory cytokine secretion and inflammatory responses [43,44]. Additionally, S100A12 directly interacts with both S100A9 [10] and CacyBP/SIP [48].…”

Section: Discussionmentioning

confidence: 99%

“…The receptor for advanced glycation end products (RAGE) and its ligands have been described as a novel pathway connecting the innate immune system with inflammatory responses. S100A12 is one of the ligands that activates RAGE, producing downstream signaling that involves key mediators such as NF-κB, MAP kinase, CD36, TLRs, and other molecules [29,30,32,34,43,45,47,48]. Because S100A12 is involved in many different diseases, such as Juvenile Rheumatoid Arthritis (JRA), asthma, Behçet's, Kawasaki disease, and IBD, it is natural that researchers would attempt to target this interaction pharmacologically [42,[78][79][80][81].…”

Section: S100a12 In Ibd (Including Crohn's and Ulcerativementioning

confidence: 99%

“…Interestingly, administration of a TLR4 blocker significantly abrogated monocyte migration due to S100A12 activation, underscoring its importance in innate immune cell activation [41]. S100A12 is also a ligand for the receptor for advanced glycation end products (RAGE) on monocytes or epithelial cells [29,32,[42][43][44]. S100A12 promotes NF-κB activation and downstream upregulation of proinflammatory cytokines such as interleukin-1β, a cytokine that is implicated in numerous gastrointestinal diseases [45,46].…”

Section: Introductionmentioning

confidence: 99%

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S100A12 in Digestive Diseases and Health: A Scoping Review

Carvalho

Francis

et al. 2020

Gastroenterology Research and Practice

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Calgranulin proteins are an important class of molecules involved in innate immunity. These members of the S100 class of the EF-hand family of calcium-binding proteins have numerous cellular and antimicrobial functions. One protein in particular, S100A12 (also called EN-RAGE or calgranulin C), is highly abundant in neutrophils during acute inflammation and has been implicated in immune regulation. Structure-function analyses reveal that S100A12 has the capacity to bind calcium, zinc, and copper, processes that contribute to nutritional immunity against invading microbial pathogens. S100A12 is a ligand for the receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and CD36, which promote cellular and immunological pathways to alter inflammation. We conducted a scoping review of the existing literature to define what is known about the association of S100A12 with digestive disease and health. Results suggest that S100A12 is implicated in gastroenteritis, necrotizing enterocolitis, gastritis, gastric cancer, Crohn’s disease, irritable bowel syndrome, inflammatory bowel disease, and digestive tract cancers. Together, these results reveal S100A12 is an important molecule broadly associated with the pathogenesis of digestive diseases.

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Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells

et al. 2021

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Myeloproliferative neoplasms (MPN), comprising essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are hematological disorders of the myeloid lineage characterized by hyperproliferation of mature blood cells. The prediction of the clinical course and progression remains difficult and new therapeutic modalities are required. We conducted a CD34+ gene expression study to identify signatures and potential biomarkers in the different MPN subtypes with the aim to improve treatment and prevent the transformation from the rather benign chronic state to a more malignant aggressive state. We report here on a systematic gene expression analysis (GEA) of CD34+ peripheral blood or bone marrow cells derived from 30 patients with MPN including all subtypes (ET (n = 6), PV (n = 11), PMF (n = 9), secondary MF (SMF; post-ET-/post-PV-MF; n = 4)) and six healthy donors. GEA revealed a variety of differentially regulated genes in the different MPN subtypes vs. controls, with a higher number in PMF/SMF (200/272 genes) than in ET/PV (132/121). PROGENγ analysis revealed significant induction of TNFα/NF-κB signaling (particularly in SMF) and reduction of estrogen signaling (PMF and SMF). Consistently, inflammatory GO terms were enriched in PMF/SMF, whereas RNA splicing–associated biological processes were downregulated in PMF. Differentially regulated genes that might be utilized as diagnostic/prognostic markers were identified, such as AREG, CYBB, DNTT, TIMD4, VCAM1, and S100 family members (S100A4/8/9/10/12). Additionally, 98 genes (including CLEC1B, CMTM5, CXCL8, DACH1, and RADX) were deregulated solely in SMF and may be used to predict progression from early to late stage MPN. Graphical abstract

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TLR4 and RAGE conversely mediate pro-inflammatory S100A8/9-mediated inhibition of proliferation-linked signaling in myeloproliferative neoplasms

Cited by 37 publications

References 27 publications

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

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

S100A12 in Digestive Diseases and Health: A Scoping Review

Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells

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