Interferon

About: Interferon is a research topic. Over the lifetime, 28969 publications have been published within this topic receiving 1219645 citations. The topic is also known as: IFN & interferons.

Interleukin 10 (IL-10) Inhibits Human Lymphocyte Interferon 3,-Production by Suppressing Natural Killer Cell Stimulatory Factor/IL-12 Synthesis in Accessory Cells By Annalisa D'Andrea, Miguel Aste-Amezaga,

Abstract: SulTlnlary Natural killer cell stimulatory factor or interleukin 12 (NKSF/IL-12) is a heterodimeric cytokine produced by monocytes/macrophages, B cells, and possibly other accessory cell types primarily in response to bacteria or bacterial products. NKSF/IL-12 mediates pleiomorphic biological activity on T and NK cells and, alone or in synergy with other inducers, is a powerful stimulator of interferon 3' (IFN-3") production. IL-10 is a potent inhibitor of monocyte-macrophage activation, that inhibits production of tumor necrosis factor ot (TNF-o 0, IL-1 and also IFN-3' from lymphocytes acting at the level of accessory cells. Because TNF-ot and IL-1 are not efficient inducers of IFN-3', the mechanism by which IL-10 inhibits IFN-3' production is not clear. In this paper, we show that IL-IO is a potent inhibitor of NKSF/IL-12 production from human peripheral blood mononuclear cells activated with Staphylococcus aureus or lipopolysaccharide (LPS). Both the production of the free NKSF/IL-12 p40 chain and the biologically active p70 heterodimer are blocked by IL-10. NKSF/IL-12 p40 chain mRNA accumulation is strongly induced by S. aureus or LPS and downregulated by IL-10, whereas the p35 mRNA is constitutively expressed and only minimally regulated by S. aureus, LPS, or IL-10. Although IL-IO is able to block the production of NKSF/IL-12, a powerful inducer of IFN-3' both in vitro and in vivo, the mechanism of inhibition of IFN-3' by IL-10 cannot be explained only on the basis of inhibition of NKSF/IL-12 because IL-10 can partially inhibit IFN-3' production induced by NKSF/IL-12, and also, the IFN-3' production in response to various stimuli in the presence of neutralizing antibodies to NKSF/IL12. Our findings that antibodies against NKSF/IL-12, TNF-o~, or IL-1~ can significantly inhibit IFN-3" production in response to various stimuli and that NKSF/IL-12 and IL-1B can overcome the IL-10-mediated inhibition of IFN-% suggest that IL-10 inhibition of IFN-3' production is primarily due to its blocking production from accessory cells of the IFN-3'-inducer NKSF/IL12, as well as the costimulating molecule IL-1/~.

Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction

Abstract: Toll-like receptors (TLRs) recognize microbial pathogens and trigger innate immune responses. Among TLR family members, TLR7, TLR8, and TLR9 induce interferon (IFN)-alpha in plasmacytoid dendritic cells (pDCs). This induction requires the formation of a complex consisting of the adaptor MyD88, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and IFN regulatory factor (IRF) 7. Here we show an essential role of IL-1 receptor-associated kinase (IRAK)-1 in TLR7- and TLR9-mediated IRF7 signaling pathway. IRAK-1 directly bound and phosphorylated IRF7 in vitro. The kinase activity of IRAK-1 was necessary for transcriptional activation of IRF7. TLR7- and TLR9-mediated IFN-alpha production was abolished in Irak-1-deficient mice, whereas inflammatory cytokine production was not impaired. Despite normal activation of NF-kappaB and mitogen-activated protein kinases, IRF7 was not activated by a TLR9 ligand in Irak-1-deficient pDCs. These results indicated that IRAK-1 is a specific regulator for TLR7- and TLR9-mediated IFN-alpha induction in pDCs.

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling

Abstract: The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutieres syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity

Abstract: We formulate a two-phase paradigm of autoimmunity associated with systemic lupus erythematosus, the archetypal autoimmune disease. The initial Toll-like receptor (TLR)-independent phase is mediated by dendritic cell uptake of apoptotic cell debris and associated nucleic acids, whereas the subsequent TLR-dependent phase serves an amplification function and is mediated by uptake of TLR ligands derived from self-antigens (principally nucleic acids) complexed with autoantibodies. Both phases depend on elaboration of type I interferons (IFNs), and therapeutic interruption of induction or activity of these cytokines in predisposed individuals might have a substantial mitigating effect in lupus and other autoimmune diseases.