Figure 2.

Schema illustrating the relationship between the OPG/TRAIL/TRAIL-R system, pericytes, growth factors, and the cytokines IL-1 and IL-6 on the balance between proliferation and apoptosis of vascular smooth muscle cells (VSMC). In the presence of inflammatory cytokines IL-1β or IL-6 and trauma or injury, activated cells express OPG. Activation of cytokine receptors IL-1R and IL-6R induces the recruitment of monocytes and neutrophils. The growth factor system, which includes vascular endothelial growth factors (VEGFs) and PDGF, influences the proliferation (angiogenesis) and OPG expression in vascular cells. Associated with the microvasculature, pericytes secrete elevated amounts of OPG. OPG also acts as a receptor for TRAIL. TRAIL binds to its receptors, TRAIL-Rs. The cellular actions of TRAIL are tightly regulated in a balance between the apoptosis and proliferation of vascular cells. TRAIL and RANKL increase matrix metalloproteinase (MMP) activity, leading to degradation of the extracellular matrix. The cellular actions promoted by IL-1β induce MMP-3 production. MMP-3 is constitutively expressed in EC and VSMC. The human monoclonal antibodies canakinumab and evolocumab, which target IL-1β, have anti-inflammatory effects. Sarilumab and tocilizumab are human monoclonal antibodies against the IL-6 receptor-α. Intracellular signaling of IL-6 in response to receptor activation is complex—anti-inflammatory protective but pro-inflammatory for the immune response.