Abstract
Background: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. Results: We found that IL-6 did not change the expression of angiogenic factors in the MNC of patients with MPN and HEL cells. However, IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors—endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)—in patients with polycythemia vera (PV). Furthermore, VEGF significantly increased the expression of HIF-1α and eNOS genes, the latter inversely regulated by PI3K and mTOR signaling in the MNC of primary myelofibrosis (PMF). VEGF and inhibitors of inflammatory JAK1/2, PI3K, and mTOR signaling reduced the eNOS protein expression in HEL cells. VEGF also decreased the expression of eNOS and HIF-1α proteins in the MNC of PMF. In contrast, VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. VEGF increased the level of IL-6 immunopositive MNC of MPN. In summary, VEGF conversely regulated gene and protein expression of angiogenic factors in the MNC of PMF, while VEGF increased angiogenic factor expression in PV mediated by the inflammation-related signaling. Conclusion: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition.
Highlights
Myeloproliferative neoplasms (MPNs) are characterized by clonal proliferation of mature blood elements from several myeloid lineages associated with increased angiogenesis [1]
According to the presented results, IL-6 does not change the level of angiogenic factors in the mononuclear cells (MNC) of MPN and human erythroleukemic (HEL) cells, as well as the phosphorylation of STAT5 and mammalian target of rapamycin (mTOR) in HEL cells, while it slightly stimulated AKT signaling
We have presented that Ruxolitinib significantly increased angiogenic factors—HIF-1α, endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF) in the presence of IL-6—while it only significantly increased the VEGF in the MNC of primary myelofibrosis (PMF) patients
Summary
Myeloproliferative neoplasms (MPNs) are characterized by clonal proliferation of mature blood elements from several myeloid lineages associated with increased angiogenesis [1]. Participation of inflammatory cells is supported by increased inteleukin-6 (IL-6) cytokine in plasma and bone marrow stroma of MPNs, which is dependent on JAK2V617F [6] These observations support further studies of inflammation-dependent angiogenesis with emphasis on proliferation-related signaling pathways as a hallmark of MPN. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors—endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)—in patients with polycythemia vera (PV). VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. Conclusion: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition
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