Expression of IL-12-related molecules in human intestinal microvascular endothelial cells is regulated by TLR3

Abstract

Members of the interleukin (IL)-12 family constitute subunits of IL-12, -23, and -27. These ILs represent pivotal mediators in the regulation of cell-mediated immune responses and in animal models of human inflammatory bowel disease. Recent work has suggested that intestinal endothelial cells might serve as a second line of defense in bacterial sensing of invading pathogens. The purpose of this study was to examine the production of IL-12 family members in intestinal endothelial cells (HIMEC). HIMEC were stimulated with proinflammatory agents (TNF-α, IFN-γ, IL-1β) and microbial antigens [LPS, lipoteichoic acid, peptidoglycan, CpG-DNA, flagellin, poly(I:C)]. Expression of IL-12 family members and of Toll-like receptor (TLR)3 in HIMEC was assessed by real-time RT-PCR, immunostaining, flow cytometry, and immunoblot analysis. HIMEC display an induction of Epstein-Barr virus-induced gene 3 (EBI3), IL-12p35, and IL-23p19, whereas no expression of IL-12p40 and IL-27p28 was detectable. The strongest induction was induced by proinflammatory factors known to utilize the NF-κB pathway, and expression of EBI3 and IL-23p19 was diminished by an NF-κB inhibitor. HIMEC display regulated expression of TLR3. Adhesion and transmigration assays showed proinflammatory responses after HIMEC stimulation. HIMEC are capable of producing IL-12 family members as a response to microbial stimuli. The TLR3 agonist, poly(I:C), was shown to enhance leukocyte adhesion in vitro in HIMEC. Our data suggest that the intestinal microvasculature is responsive to ligands of TLR3 expressed on intestinal endothelial cells, thereby adding to the regulation of adaptive immunity and leukocyte recruitment.

Level of Interleukin‐35 in Gingival Crevicular Fluid, Saliva, and Plasma in Periodontal Disease and Health

“…The housekeeping cytokines, for example TGF‐β, prevent the formation of inflammation, whereas the responsive cytokines, including new cytokine IL‐35, repress full‐blown inflammation. The other studies 30‐33 about IL‐35 expression in the literature support their results. IL‐35 was induced by bacterial lipopolysaccharides and stimulations of different proinflammatory cytokines in Treg cells, 30 smooth muscle cells, 31 microvascular endothelial cells, 32 and monocytes 33 .…”

Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth

“…Coupled with our earlier demonstration that 21-nt siRNAs inhibit hemangiogenesis in mouse models of choroidal and dermal neovascularization, as well the widespread expression of TLR3 on both vascular endothelial cells from various tissue beds (12,28,31,32), it is likely that these RNA duplexes are generic inhibitors of both components of neovascularization. Such target-independent antiangiogenic activities can be serendipitous, as in the case of corneal neovascularization, which is responsible for blindness in nearly 10 million people (33) and promotes rejection of corneal allografts, the most commonly transplanted solid tissue.…”

Role of the vascular and lymphatic endothelium in the pathogenesis of inflammatory bowel disease: 'brothers in arms'

“…However, the expression patterns of different TLRs vary depending on the origin of the VECs. Expression of the bacterial flagellin receptor, TLR5, and the double-stranded RNA receptor, TLR3, has been specifically demonstrated on the surface of HIMECs 100 101. Indeed, TLR3 on the surface of HIMECs can modulate the expression of IL-12 and related molecules by these cells 101.…”

“…Expression of the bacterial flagellin receptor, TLR5, and the double-stranded RNA receptor, TLR3, has been specifically demonstrated on the surface of HIMECs 100 101. Indeed, TLR3 on the surface of HIMECs can modulate the expression of IL-12 and related molecules by these cells 101. Activation of TLR5 expressed on the surface of dermal VECs upregulated expression of ICAM-1, although this was not shown in HIMECs 100…”