Activation of Toll-Like Receptor 3 Induces Interleukin-1 Receptor Antagonist Expression by Activating the Interferon Regulatory Factor 3

Abstract

Toll-like receptor 3 (TLR3) is a sensor of endogenous cell necrosis during the process of acute inflammation. Interleukin (IL)-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine and can negatively regulate the pathogenesis of inflammation. However, whether and how activation of TLR3 can regulate IL-1Ra expression has not been clarified. Here, we show that poly(I:C) induces IL-1Ra expression in primarily cultured human fibroblast-like synoviocytes and other types of cells. Induction of IL-1Ra by poly(I:C) was dependent on TLR3, but was independent of melanoma differentiationassociated protein 5 or retinoic acid-inducible gene I. Interferon regulatory factor 3 (IRF3) directly binds to the IL-1Ra promoter and promotes IL-1Ra expression in response to poly(I:C) stimulation. Induction of IL-1Ra by poly(I:C) was abolished by the inhibition of the NF-κB signaling, attenuated by the inhibition of the PI3K-Akt signaling, enhanced by inhibition of the ERK1/2 or MSK1/2 activation, but was independent of the p38 MAPK signaling. Treatment with poly(I:C) or Sendai virus elevated the levels of serum IL-1Ra in wildtype, but not in TLR3 -/or IRF3 -/mice. Our findings may provide new insights into the intrinsic anti-inflammatory function of TLR3 and double-stranded RNA-induced IL-Ra expression by TLR3 and its regulation.

The Role of TNF-α in the Pathogenesis of Temporomandibular Disorders

“…30) Moreover, TNF-α is able to upregulate crucial integrins and adhesion molecules on vascular endothelium, including E-selectin and vascular cell adhesion molecule-1 (VCAM-1), which can promote the production of more chemokines to enhance inflammation. 40) Interestingly, some studies have reported that TNF-α can regulate anti-inflammatory mediator interleukin-1Ra (IL-1Ra) in vitro, 41,42) signifying a complicated role TNF-α plays in the development of inflammation. 43) TNF-α also reduces the production of stromal cell-derived factor-1 (SDF-1) in rats, 25) which can induce neutrophil migration and attract leukocytes from the blood into the inflamed tissue.…”

“…SDF-1 (stromal cell-derived factor-1) 25) NF-κB Induces the neutrophil migration In vitro & in vivo Attracts leukocytes from the blood into the inflamed tissue IL-1Ra (Interleukin-1Ra) 41,42) NF-κB Inhibits the inflammation and connective tissue degradation In vitro TLR4: toll-like receptor 4; MyD88: myeloid differentiation factor; NF-κB B: nuclear factor-kappa B; p38 MAPK: p38 mitogen-activated protein kinase; JNK: Janus Kinase; ERK: extracellular signal-regulated kinases; JAK2: Janus kinase 2; PI3K/Akt: phosphatidylinositol-3 kinase/protein kinase B. TMJ. 45) Simultaneously, mandibular condylar cartilage of the human patients was degraded excessively.…”

Toll‐like receptors (TLRs): An old family of immune receptors with a new face in cancer pathogenesis

“…It has been shown that CpG‐DNA–mediated activation of TLR9 not only increased the expression of Bax but also induced caspase‐dependent apoptotic cell death in murine macrophages 75 . Moreover, the interaction of TLR3 with dsRNA triggers a cascade to activate a wide range of downstream axes, such as p38, JNK and IFN regulatory factors, which in turn regulate apoptosis in cancer cells 76 . TLR3‐poly I:C interaction also enhances the therapeutic value of the conventional antitumour agent cycloheximide in different human and murine tumour cell lines through increasing the production of IFN‐γ, a well‐known cytokine which its association with caspase and p53 has been previously well‐established 77 …”

Once Upon a Time

“…However, also innate immunity plays important roles in mounting protection against viral infections. For instance, it was recently reported that Tollip, a negative immune regulator, can inhibit the proinflammatory response to rhinovirus infection [1], that toll-like receptor 3 can induce interleukin (IL)-1 receptor antagonist expression leading to an induction of anti-inflammatory reactions [2], and that gender-specific hormones such as 17β-estradiol can modulate the innate immune response to viral infections [3]. In addition, we also published that interferons are crucial players in the fight against viral infections as they enhance the innate immune response against many viral pathogens [4-6].…”