interleukin-8 and Myeloproliferative-Disorders

Previously, the family of S100A 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 S100A4, S100A8, S100A9 and S100A12 in myeloproliferative neoplasms (MPNs) in order to assess the involvement of chronic inflammation in the pathogenesis of MPN.. We analyzed the S100A4, S100A8, S100A9 and S100A12 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.. From our data we conclude that the S100A8 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 S100A8/9-mediated inhibition of the proliferation-related AKT and ERK1/2 signaling pathways can be decreased by CALR mutation-dependent TLR4 blocking and increased by RAGE inhibition in MPN.

Topics: Adult; Aged; Aged, 80 and over; Blotting, Western; Calgranulin A; Calgranulin B; Cell Proliferation; Female; Humans; Immunohistochemistry; Interleukin-8; Male; Middle Aged; Myeloproliferative Disorders; Receptor for Advanced Glycation End Products; Signal Transduction; Toll-Like Receptor 4; Young Adult

The neutrophil superoxide (O2-)-producing capacity in 57 patients with chronic myeloproliferative disorders (MPDs) and eight patients with chronic myelomonocytic leukemia (CMML) was investigated. O2- release in neutrophils stimulated by chemotactic peptide was markedly increased in all types of chronic MPD, including chronic myelogenous leukemia in both chronic phase and blastic crisis, polycythemia vera, and essential thrombocythemia, but was normal in CMML, which is thought to be a myelodysplastic disorder rather than MPD. Increase in O2(-)-producing capacity in MPD was also observed when other receptor-mediated agonists such as interleukin-8 and concanavalin A were used, but not when phorbol ester, a direct activator of protein kinase C, was used as the triggering agonist of O2- release. Priming effects of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), and tumor necrosis factor (TNF) on chemotactic peptide-induced O2- release was observed in all patients with MPD and CMML, though fold enhancement of priming effects was much less in MPD compared with normal subjects. In addition, the priming effects of TNF were less than those of GM-CSF in 10 cases, whereas the priming effects of TNF were consistently and markedly greater than those of GM-CSF in normal subjects. Tyrosine phosphorylation of 42-kDa protein stimulated by G-CSF, GM-CSF, and TNF was observed in CML neutrophils to be identical to that in normal neutrophils. Present results indicate specific potentiation of the receptor-mediated route of signaling that is linked to the respiratory burst and downregulated responsiveness to cytokines in neutrophils in patients with all types of chronic MPD, suggesting in vivo priming of patient neutrophils via certain mechanism by cytokines or related stimuli in these hematological disorders.

Topics: Concanavalin A; Cytokines; Humans; Interleukin-8; Myeloproliferative Disorders; Neutrophil Activation; Neutrophils; Receptors, Cell Surface; Respiratory Burst; Signal Transduction; Superoxides