Endothelial barrier disruptive effect of IFN-ƴ and TNF-α: synergism of pro-inflammatory cytokines

Crosstalk and synergy between interferon-γ (IFN-Ƴ) and tumor necrosis factor-α (TNF-α) in endothelial cells have previously been documented, however, there is an absence of articles reviewing the synergistic effect of IFN-Ƴ and TNF-α in regulating the endothelial barrier function. This review discusses the regulatory mechanisms and recent evidence of the synergism of IFN-γ and TNF-α in causing destabilization of endothelial junctions in various clinical studies and preclinical models. Articles were retrieved from electronic databases such as Web of Science, PubMed, Google Scholar, and Scopus. The search terms used were “interferon”, “interferon-gamma”, “tumor necrosis factor-α”, “vascular inflammation”, “endothelial barrier”, “endothelial permeability” and “synergism”. We selected articles published between 2004 and 2024. Through the Rho-associated protein kinase (ROCK) and p38 mitogen-activated protein (MAP) kinase pathways, our results showed that IFN-γ controls the remodeling of actin and the stability of junctions. In comparison to IFN-γ, the signaling cascades triggered by TNF-α involve a variety of pathways such as nuclear factor-kappa B (NF-κB), small GTPases, tyrosine kinases, integrin receptors, and barrier-stabilizing molecules such as Ras-related proteins 1A (Rap1A) and Rac family small GTPase 1 (Rac1). In the context of IFN-γ and TNF-α synergism, combined IFN-γ and TNF-α alter adherens and tight junctions. It is deduced that c-Jun N-terminal kinase (JNK), signal transducers and activators of transcription (STAT1), and caspase signaling pathways regulate endothelial barrier disruption caused by IFN-γ and TNF-α. Collectively, the mechanism underlying the synergistic action of IFN-γ and TNF-α is still lacking. Future work is needed to explore the crosstalk pathways of IFN-γ and TNF-α involved in the regulation of endothelial barrier function such as modulation of extracellular matrix (ECM) structure, involvement of tyrosine kinases and roles of small GTPases.

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