An inhibitory alternative splice isoform of Toll-like receptor 3 is induced by type I interferons in human astrocyte cell lines

Abstract

Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA. It stimulates pro-inflammatory cytokine and interferon production. Here we reported the expression of a novel isoform of TLR3 in human astrocyte cell lines whose message is generated by alternative splicing. The isoform represents the N-terminus of the protein. It lacks many of the leucine-rich repeat domains, the transmembrane domain, and the intracellular Toll/interleukin-1 receptor domain of TLR3. Type I interferons (interferon-α and interferon-β) induced the expression of this isoform. Exogenous overexpression of this isoform inhibited interferon regulatory factor 3, signal transducers and activators of transcription 1, and Inhibitor of kappa B α signaling following stimulation. This isoform of TLR3 also inhibited the production of chemokine interferon-γ-inducible protein 10. Our study clearly demonstrated that the expression of this isoform of TLR3 was a negative regulator of signaling pathways and that it was inducible by type I interferons. We also found that this isoform could modulate inflammation in the brain. [BMB Reports 2015; 48(12): 696-701]

Global Proteomic and Methylome Analysis in Human Induced Pluripotent Stem Cells Reveals Overexpression of a Human TLR3 Affecting Proper Innate Immune Response Signaling

“…B) pathways play an essential role in TLR3‐mediated gene induction . The loss of inflammation response of cells to bacterial (LPS) or viral (Poly (IC) infection has been shown before in specific mouse neural cell types that overexpress a different mutant mouse TLR3 isoform to the human TLR3 isoform described in this study (not expressed in mice) . Interestingly, a recent study found that differentiation of human iPSC results in a loss of immunogenicity and leads to the induction of tolerance, despite expected antigen expression differences between iPSC‐derived versus original somatic cells .…”

“…Given that it has been previously published that a short isoform of mouse TLR3, but different sequence and size to the human TLR3 isoform described in this study can act as a suppressor of the TLR3 innate immune pathway by competing with the full length TLR3 protein in mouse astrocytes , we next assessed the functional immune response of inflammation cytokine IL6 in human iPSC‐NSC to Poly (I:C) and LPS. Assessment of IL6 expression levels by ELISA demonstrated that iPSC‐derived cells (F2 cells) have significantly higher levels of expression of IL6 compared to F1 cells and a suppressed innate immune response to viral infection (Poly IC 1ug/ml overnight) in iPSC‐derived cells (Fig.…”

Protective effect of ginsenoside Rh3 against anticancer drug-induced apoptosis in LLC-PK1 kidney cells

“…Cotreatment with the ginsenoside Rh3 markedly decreased cisplatin-induced phosphorylation of JNK and ERK MAPKs (Fig. 2) that are well defined representative inflammation markers [21], [22]. Recently, ginsenoside Rh3 was reported to inhibit the expressions of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-6) in lipopolysaccharide-stimulated microglia [21].…”

Celastrol suppresses expression of adhesion molecules and chemokines by inhibiting JNK-STAT1/NF-κB activation in poly(I:C)-stimulated astrocytes

“…At the same time, celastrol was not able to reduce poly(I:C)-induced phosphorylation of ERK and p38, but it rather led to increased phosphorylation of ERK and p38 MAPKs in the treated cells. Previous studies reported JNK mediating poly(I:C)-induced activation of STAT1 ( 17 , 18 ), with poly(I:C) stimulation, STAT1 transcription factor plays a significant role in the expression of various pro-inflammatory mediators in astrocytes ( 7 , 8 , 19 ). Therefore, we next investigated the effect of celastrol on poly(I:C)-induced STAT1 activation.…”