Effect of pro-inflammatory cytokines TNF-a and IL-1b on endothelial cells

Beloglazova IB, Dergilev KV, Goltseva YuD, Zubkova ES, Kiselev IS, Kruchinin SN, Parfyonova YeV. Effect of pro-inflammatory cytokines TNF-a and IL-1b on endothelial cells. Russian Cardiology Bulletin. 2024;19(4‑2):121‑127. (In Russ.)
https://doi.org/10.17116/Cardiobulletin202419042121

Подписка 2026 Кардиологический вестник (Russian Cardiology Bulletin)

Использование инфографики авторами научных работ

Close metadata

BACKGROUND

Endothelial dysfunction is essential in pathogenesis of numerous chronic diseases, including cardiovascular ones, and precedes clinical manifestations. Among numerous causes of endothelial dysfunction, chronic inflammation, including latent microvascular inflammation, is important regarding exposure of endothelial cells to pro-inflammatory factors. Although the role of inflammation in endothelial dysfunction has been studied for several years, many questions remain unanswered regarding molecular mechanisms underlying the effects of specific cytokines on endothelial cells.

OBJECTIVE. T

O investigate the long-term effects of pro-inflammatory factors TNF-a and IL-1b on expression profile, intracellular signaling and angiogenic properties of endothelial cells.

MATERIAL AND METHODS

We used a 2D model of angiogenesis based on co-culture of human umbilical vein endothelial cells (HUVECs) and mesenchymal stromal cells. Gene expression was analyzed using real-time PCR. Proteomic analysis of kinase phosphoforms was conducted to evaluate intracellular signaling in HUVECs in response to IL-1b and TNF-a exposure.

RESULTS

Pro-inflammatory cytokines reduced angiogenic properties of endothelial cells after 2—4-day exposure. The effect of IL-1b was even more obvious. Additionally, IL-1b stimulated activation of genes associated with endothelial-mesenchymal transition largely than TNF-a. Endothelial-mesenchymal transition contributes to myocardial perivascular fibrosis. Both cytokines differentially affected CREB-mediated intracellular signaling.

CONCLUSION

Prolonged exposure of endothelial cells to pro-inflammatory factors TNF-a and IL-1b impairs their angiogenic properties. Notably, the effect of IL-1b was clearer. This is likely explained by different effects of these cytokines on expression of EnMT-associated genes and CREB-mediated intracellular signaling.

Keywords:

co-culture

angiogenesis

MSC

HUVEC

Il-1b

TNF-a

inflammation

Authors:

Beloglazova I.B.

Chazov National Medical Research Center of Cardiology

ORCID: 0000-0002-2345-3681

Dergilev K.V.

Chazov National Medical Research Center of Cardiology

ORCID: 0000-0003-2712-4997

Goltseva Yu.D.

Chazov National Medical Research Center of Cardiology

ORCID: 0000-0002-6367-3785

Zubkova E.S.

Chazov National Medical Research Center of Cardiology

ORCID: 0000-0002-0512-3670

Kiselev I.S.

Chazov National Medical Research Center of Cardiology

ORCID: 0000-0003-3366-4113

Kruchinin S.N.

Chazov National Medical Research Center of Cardiology

ORCID: 0009-0006-1583-6582

Parfyonova Ye.V.

Chazov National Medical Research Center of Cardiology;
Lomonosov Moscow State University

ORCID: 0000-0002-0969-5780

Received:

25.10.2024

Accepted:

28.10.2024

Close metadata

References:

Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, Nishigaki I. The vascular endothelium and human diseases. International Journal of Biological Sciences. 2013;9(10):1057-1069. https://doi.org/10.7150/ijbs.7502
Theofilis P, Sagris M, Oikonomou E, Antonopoulos AS, Siasos G, Tsioufis C, Tousoulis D. Inflammatory Mechanisms Contributing to Endothelial Dysfunction. Biomedicines. 2021;9(7):781. https://doi.org/10.3390/biomedicines9070781
Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Medicine. 2007;(8):952-961. https://doi.org/10.1038/nm1613
Markwald RR, Fitzharris TP, Manasek FJ. Structural development of endocardial cushions. American Journal of Anatomy. 1977;148(1):85-119. https://doi.org/10.1002/aja.1001480108
Moore-Morris T, Guimarães-Camboa N, Banerjee I, Zambon AC, Kisseleva T, Velayoudon A, Stallcup WB, Gu Y, Dalton ND, Cedenilla M, Gomez-Amaro R, Zhou B, Brenner DA, Peterson KL, Chen J, Evans SM. Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. The Journal of Clinical Investigation. 2014;124(7):2921-2934. https://doi.org/10.1172/JCI74783
Tombor LS, John D, Glaser SF, Luxán G, Forte E, Furtado M, Rosenthal N, Baumgarten N, Schulz MH, Wittig J, Rogg EM, Manavski Y, Fischer A, Muhly-Reinholz M, Klee K, Looso M, Selignow C, Acker T, Bibli SI, Fleming I, Patrick R, Harvey RP, Abplanalp WT, Dimmeler S. Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction. Nature Communication. 2021;12(1):681. https://doi.org/10.1038/s41467-021-20905-1
Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Medicine. 2007;13(8):952-961. https://doi.org/10.1038/nm1613
Mahler GJ, Farrar EJ, Butcher JT. Inflammatory cytokines promote mesenchymal transformation in embryonic and adult valve endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33(1):121-30. https://doi.org/10.1161/ATVBAHA.112.300504
Maleszewska M, Moonen JR, Huijkman N, van de Sluis B, Krenning G, Harmsen MC. IL-1β and TGF-β2 synergistically induce endothelial to mesenchymal transition in an NFκB-dependent manner. Immunobiology. 2013;218(4):443-54. https://doi.org/10.1016/j.imbio.2012.05.026
Sánchez-Duffhues G, García de Vinuesa A, van de Pol V, Geerts ME, de Vries MR, Janson SG, van Dam H, Lindeman JH, Goumans MJ, Ten Dijke P. Inflammation induces endothelial-to-mesenchymal transition and promotes vascular calcification through downregulation of BMPR2. The Journal of Pathology. 2019;247(3):333-346. https://doi.org/10.1002/path.5193
Zubkova E, Dergilev K, Beloglazova I, Kalinin A, Guseva A, Andreev A, Partigulov S, Lepilin M, Menshikov M, Parfyonova Y. Paracrine Responses of Cardiosphere-Derived Cells to Cytokines and TLR Ligands: A Comparative Analysis. International Journal of Molecular Sciences. 2023;24(24):17278. https://doi.org/10.3390/ijms242417278
Beloglazova I, Stepanova V, Zubkova E, Dergilev K, Koptelova N, Tyurin-Kuzmin PA, Dyikanov D, Plekhanova O, Cines DB, Mazar AP, Parfyonova Y. Mesenchymal stromal cells enhance self-assembly of a HUVEC tubular network through uPA-uPAR/VEGFR2/integrin/NOTCH crosstalk. Biochimica et Biophysica Acta. Molecular Cell Research. 2022;1869(1):119157. https://doi.org/10.1016/j.bbamcr.2021.119157
Beloglazova I, Zubkova E, Dergilev K, Goltseva Y, Parfyonova Y. New Insight on 2D In Vitro Angiogenesis Models: All That Stretches Is Not a Tube. Cells. 2022;11(20):3278. https://doi.org/10.3390/cells11203278
Stratman AN, Schwindt AE, Malotte KM, Davis GE. Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood. 2010;116(22):4720-30. https://doi.org/10.1182/blood-2010-05-286872
Pires BRB, Silva RCMC, Ferreira GM, Abdelhay E. NF-kappaB: Two Sides of the Same Coin. Genes (Basel). 2018;9(1):24. https://doi.org/10.3390/genes9010024
Chowdhury MAR, Haq MM, Lee JH, Jeong S. Multi-faceted regulation of CREB family transcription factors. Frontiers in the Molecular Neuroscience. 2024;17:1408949. https://doi.org/10.3389/fnmol.2024.1408949
Scoditti E, Massaro M, Carluccio MA, Distante A, Storelli C, De Caterina R. PPARgamma agonists inhibit angiogenesis by suppressing PKCalpha- and CREB-mediated COX-2 expression in the human endothelium. Cardiovascular Research. 2010;86(2):302-310. https://doi.org/10.1093/cvr/cvp400