TNF-α in the cardiovascular system: from physiology to therapy

Figures & data

Figure 1 TNF-α-initiated signal transduction. TNF-α (soluble or membrane-bound) activates two different TNF-receptors, ie, TNFR1 and TNFR2. After binding of TNF-α, TNFR1 recruits distinct adaptor molecules (TRAF2, TRADD) at the intracellular death domain, thereby activating three major signaling pathways: NF-κB-signaling, MAPK/C-Jun-signaling, and caspase/apoptotic signaling. TNFR2 activation by membrane-bound TNF-α leads to activation of PI3K/Akt and proangiogenic pathways (eg, VEGF/VEGFR2), and is furthermore able to interfere with NF-κB signaling.

Abbreviations: Akt, protein kinase B; AP-1, activator protein-1; Etk, endothelial/epithelial tyrosine kinase; ERK, extracellular signal-regulated kinase; FADD, Fas-associated protein with death domain; IKK, IκB kinase; IκBα, inhibitor of κB; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; RIP, receptor-interacting protein kinase; SODD, silencer of death domains; TNF-α, tumor necrosis factor alpha; TNFR, TNF-α receptor; TRADD, TNFR1-associated death domain protein; TRAF2, TNFR-associated factor 2; VEGFR2, vascular endothelial growth factor receptor 2.

Figure 2 Shear stress dependency of TNF-α signaling in endothelial cells. (A) Laminar shear stress prevents proinflammatory activation of endothelial cells by TNF-α by inhibiting NF-κB signaling (eg, preventing expression of adhesion molecules and inducing production of NO) and therefore results in a quiescent endothelial phenotype. (B) Proatherogenic non-uniform shear stress synergistically enhances proinflammatory TNF-α signaling by activating NF-κB, AP-1, or c-Jun, leading to endothelial dysfunction characterized by increased permeability, enhanced oxidative stress, lack of cell alignment with flow and adhesion molecule expression, followed by adhesion of leukocytes to the activated endothelium.

Abbreviations: Akt, protein kinase B; AP-1, activator protein-1; c-Src, proto-oncogene tyrosine-protein kinase Src; eNOS, endothelial nitric oxide synthase; FAK, focal adhesion kinase; ICAM-1, intercellular adhesion molecule-1; KLF-2, Krüppel-like factor 2; NF-κB, nuclear factor-κB; NO, nitric oxide; NOX, NADPH-dependent oxidase; PECAM-1, platelet-endothelial adhesion molecule-1; PI3K, phosphatidylinositol 3-kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homolog family member A; TNF-α, tumor necrosis factor alpha; TRAF; TNFR-associated factor 2; VCAM-1, vascular cell adhesion molecule-1; VE-cadherin, vascular endothelial cadherin; VEGFR2, vascular endothelial growth factor receptor 2.

Figure 3 Schematic presentation of the most important effects elicited by TNF-α in the cells of cardiovascular system.