VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms
Аутори
Subotički, TijanaMitrović-Ajtić, Olivera
Živković, Emilija
Diklić, Miloš
Đikić, Dragoslava
Tošić, Milica
Beleslin-Čokić, Bojana
Dragojević, Teodora
Gotić, Mirjana
Santibanez, Juan F.
Čokić, Vladan
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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 mye...lofibrosis (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.
Кључне речи:
angiogenesis / IL-6 / myeloproliferative neoplasm / Ruxolitinib / VEGFИзвор:
International Journal of Molecular Sciences, 2021, 22, 13, 6671-Издавач:
- MDPI
Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200015 (Универзитет у Београду, Институт за медицинска истраживања) (RS-MESTD-inst-2020-200015)
Институција/група
Institut za medicinska istraživanjaTY - JOUR AU - Subotički, Tijana AU - Mitrović-Ajtić, Olivera AU - Živković, Emilija AU - Diklić, Miloš AU - Đikić, Dragoslava AU - Tošić, Milica AU - Beleslin-Čokić, Bojana AU - Dragojević, Teodora AU - Gotić, Mirjana AU - Santibanez, Juan F. AU - Čokić, Vladan PY - 2021 UR - http://rimi.imi.bg.ac.rs/handle/123456789/1136 AB - 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. PB - MDPI T2 - International Journal of Molecular Sciences T1 - VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms IS - 13 SP - 6671 VL - 22 DO - 10.3390/ijms22136671 ER -
@article{ author = "Subotički, Tijana and Mitrović-Ajtić, Olivera and Živković, Emilija and Diklić, Miloš and Đikić, Dragoslava and Tošić, Milica and Beleslin-Čokić, Bojana and Dragojević, Teodora and Gotić, Mirjana and Santibanez, Juan F. and Čokić, Vladan", year = "2021", 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.", publisher = "MDPI", journal = "International Journal of Molecular Sciences", title = "VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms", number = "13", pages = "6671", volume = "22", doi = "10.3390/ijms22136671" }
Subotički, T., Mitrović-Ajtić, O., Živković, E., Diklić, M., Đikić, D., Tošić, M., Beleslin-Čokić, B., Dragojević, T., Gotić, M., Santibanez, J. F.,& Čokić, V.. (2021). VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms. in International Journal of Molecular Sciences MDPI., 22(13), 6671. https://doi.org/10.3390/ijms22136671
Subotički T, Mitrović-Ajtić O, Živković E, Diklić M, Đikić D, Tošić M, Beleslin-Čokić B, Dragojević T, Gotić M, Santibanez JF, Čokić V. VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms. in International Journal of Molecular Sciences. 2021;22(13):6671. doi:10.3390/ijms22136671 .
Subotički, Tijana, Mitrović-Ajtić, Olivera, Živković, Emilija, Diklić, Miloš, Đikić, Dragoslava, Tošić, Milica, Beleslin-Čokić, Bojana, Dragojević, Teodora, Gotić, Mirjana, Santibanez, Juan F., Čokić, Vladan, "VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms" in International Journal of Molecular Sciences, 22, no. 13 (2021):6671, https://doi.org/10.3390/ijms22136671 . .