TLR4 and RAGE conversely mediate pro-inflammatory S100A8/9-mediated inhibition of proliferation-linked signaling in myeloproliferative neoplasms
Autor: | Danijela Lekovic, Mirjana Gotic, Bojana B. Beleslin-Cokic, Olivera Mitrovic-Ajtic, Dragoslava Djikić, Pascal Mossuz, Marijana Kovačić, Tijana Subotički, Miloš Diklić, Vladan P. Čokić |
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Rok vydání: | 2018 |
Předmět: |
Adult
Male 0301 basic medicine Cancer Research Blotting Western Receptor for Advanced Glycation End Products Myeloproliferative neoplasm Inflammation Granulocyte Young Adult 03 medical and health sciences 0302 clinical medicine ERK1/2 signaling medicine Calgranulin B Humans Calgranulin A AKT signaling Protein kinase B PI3K/AKT/mTOR pathway Aged Cell Proliferation Aged 80 and over Myeloproliferative Disorders biology Chemistry Interleukin-8 food and beverages General Medicine Middle Aged Immunohistochemistry S100A proteins 3. Good health Toll-Like Receptor 4 030104 developmental biology medicine.anatomical_structure Oncology biology.protein Cancer research TLR4 Molecular Medicine Female Myelopoiesis Signal transduction medicine.symptom Calreticulin Signal Transduction 030215 immunology |
Zdroj: | Cellular Oncology |
ISSN: | 2211-3436 2211-3428 |
Popis: | Purpose Previously, the family of S 100A proteins has been found to be associated with inflammation and myelopoiesis and to be able to induce or support myeloproliferation during chronic inflammation. Here, we studied the inflammatory myeloid-related proteins Si 00A4, S 100A8, S 100A9 and S100Al2 in myeloproliferative neoplasms (MPNs) in order to assess the involvement of chronic inflammation in the pathogenesis of MPN. Methods We analyzed the S100A4, S100A8, S100A9 and S100Al2 mRNA and protein levels in the bone marrow and circulation of 140 patients with MPN and 15 healthy controls using Western blotting, microarray-based mRNA expression profiling and ELISA assays, respectively. In addition we performed functional studies on the proliferation-related AKT and ERK1/2 signaling pathways in MPN-derived granulocytes using Western blotting and proteomic analyses. Results We found that the S100A mRNA levels were increased in MPN patient-derived circulatory CD34(+ )cells, and that their protein expression levels were also augmented in their granulocytes and bone marrow stroma cells, depending on the JAK2V617F mutation allele burden. We also found that calreticulin (CALR) mutations were related to reduced S100A8 plasma levels in primary myelofibrosis (PMF). The S100A8 plasma levels were found to be increased in MPN, the S100A9 plasma levels in PMF and essential thrombocythemia (ET), and the S100A12 plasma levels in polycythemia vera (PV). These 5100A plasma levels showed a positive correlation with the systemic inflammation marker IL-8, as well as with the numbers of leukocytes and thrombocytes, depending on the JAK2V617F mutation status. Additionally, we found that heterodimeric S100A8/9 can inhibit the AKT pathway in MPN-derived granulocytes mediated by the Toll-like receptor 4 (TLR4), depending on the CALR mutation status. Conversely, we found that blocking of the receptor for advanced glycation end products (RAGE) increased the S100A8/9-mediated inhibition of AKT signaling in the MPN-derived granulocytes. Moreover, we found that heterodimeric S100A8/9 generally induced TLR4-mediated ERK1/2 dephosphorylation proportionally to the JAK2V617F mutation allele burden. TLR4/RAGE blocking prevented the S100A8/9-mediated inhibition of ERK1/2 phosphorylation in PV. Conclusions From our data we conclude that the 5100A8 and S100A9 granulocyte and plasma levels are increased in MPN patients, along with inflammation markers, depending on their JAK2V617F mutation allele burden. We also found that SIO0A8/9-mediated inhibition of the proliferation-related AKT and ERK1/2 signaling pathways can be decreased by CALR mutationdependent TLR4 blocking and increased by RAGE inhibition in MPN. |
Databáze: | OpenAIRE |
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