Interferons α/β and their receptors: place in the hierarchy of cytokines

Zav’yalov, Vladimir P.; Zav’yalova, Galina A.

doi:10.1111/j.1699-0463.1997.tb00556.x

Cited by 10 publications

(2 citation statements)

References 215 publications

(161 reference statements)

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“…The effects of thymosin ␣ 1 on DCs are consistent with its antiapoptotic activity 40 as well as with its ability to induce prostaglandins 41 and to share structural homology with human IFN-␣, 42 both agents known to induce DCs maturation. 15 Given that DCs are central in the balancing act between immunopathology, immunity, and autoimmunity, 43 and that PDCs signaling through TLR9 are present in the thymus, 44 the ability to modulate DC functioning qualifies thymosin ␣ 1 as a novel endogenous regulator of the innate and adaptive immune systems acting through TLR exploitation.…”

Section: Discussionsupporting

confidence: 55%

Thymosin α 1 activates dendritic cells for antifungal Th1 resistance through Toll-like receptor signaling

Romani

Bistoni²,

Gaziano³

et al. 2004

Blood

189

217

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Dendritic cells (DCs) show a remarkable functional plasticity in the recognition of Aspergillus fumigatus and orchestrate the antifungal immune resistance in the lungs. Here, we show that thymosin alpha 1, a naturally occurring thymic peptide, induces functional maturation and interleukin-12 production by fungus-pulsed DCs through the p38 mitogen-activated protein kinase/nuclear factor (NF)-kappaB-dependent pathway. This occurs by signaling through the myeloid differentiation factor 88-dependent pathway, involving distinct Toll-like receptors. In vivo, the synthetic peptide activates T-helper (Th) cell 1-dependent antifungal immunity, accelerates myeloid cell recovery, and protects highly susceptible mice that received hematopoietic transplants from aspergillosis. By revealing the unexpected activity of an old molecule, our finding provides the rationale for its therapeutic utility and qualify the synthetic peptide as a candidate adjuvant promoting the coordinated activation of the innate and adaptive Th immunity to the fungus.

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Section: Discussionsupporting

confidence: 55%

Thymosin α 1 activates dendritic cells for antifungal Th1 resistance through Toll-like receptor signaling

Romani

Bistoni²,

Gaziano³

et al. 2004

Blood

189

217

View full text Add to dashboard Cite

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“…Replacing Arg33 by Ala in the huIFN-␣2 (YNS) destabilizes the binding more than any other mutation in the huIFN-␣2 (23 ). Previous attention was drawn to Leu30 in the huIFN-␣2 (the equivalent of Leu32 in the huIFN-), which is conserved in all type I IFNs (19,21 ). In a crystal structure of the ternary complex, both amino acids bind to similar hydrophobic clusters in IFNAR2 (23 ).…”

Section: Type I Ifns and Their Receptorsmentioning

confidence: 99%

Interferon-Inducible Myxovirus Resistance Proteins: Potential Biomarkers for Differentiating Viral from Bacterial Infections

et al. 2019

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BACKGROUND In 2015, the 68th World Health Assembly declared that effective, rapid, low-cost diagnostic tools were needed for guiding optimal use of antibiotics in medicine. This review is devoted to interferon-inducible myxovirus resistance proteins as potential biomarkers for differentiating viral from bacterial infections. CONTENT After viral infection, a branch of the interferon (IFN)-induced molecular reactions is triggered by the binding of IFNs with their receptors, a process leading to the activation of mx1 and mx2, which produce antiviral Mx proteins (MxA and MxB). We summarize current knowledge of the structures and functions of type I and III IFNs. Antiviral mechanisms of Mx proteins are discussed in reference to their structural and functional data to provide an in-depth picture of protection against viral attacks. Knowing such a mechanism may allow the development of countermeasures and the specific detection of any viral infection. Clinical research data indicate that Mx proteins are biomarkers for many virus infections, with some exceptions, whereas C-reactive protein (CRP) and procalcitonin have established positions as general biomarkers for bacterial infections. SUMMARY Mx genes are not directly induced by viruses and are not expressed constitutively; their expression strictly depends on IFN signaling. MxA protein production in peripheral blood cells has been shown to be a clinically sensitive and specific marker for viral infection. Viral infections specifically increase MxA concentrations, whereas viruses have only a modest increase in CRP or procalcitonin concentrations. Therefore, comparison of MxA and CRP and/or procalcitonin values can be used for the differentiation of infectious etiology.

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Negative modulation of signal transduction via interleukin splice variation

2007

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Interleukin 6 (IL-6) belongs to a large group of secreted proteins called cytokines functioning to mediate and regulate immunity, inflammation, and hematopoiesis with direct effects on cell proliferation, apoptosis, and differentiation. Along with the IL-6 protein, two of its splice variants, IL-6delta2 and IL-6delta4, were reported to be transcribed or expressed in vivo in human, and the mRNAs of IL-6delta3 and IL-6delta5 had been observed in mouse. While the existence of different splice variants of IL-6 has been shown, very little is known on how the structural modifications of IL-6 resulting from the formation of the different splice variants may alter cytokine functions. We have analyzed the potential effects splicing would have on interactions with the cell surface receptor complex. We (1) constructed three-dimensional structures of the IL-6 splice variants, IL-6delta2, IL-6delta3, and IL-6delta4, with the assumption that an interleukin splice variant as a folded protein should retain a functional hydrophobic core; (2) reconstructed the ternary structural complexes consisting of the modeled IL-6 splice variants, the IL-6 receptor molecule (IL-6R) and the dimeric signal-transducing protein, gp130, and (3) analyzed all complexes and made comparisons with the X-ray structure of the wild-type IL-6 complex. We identified three separate sites on IL-6 where interactions are made with IL-6R and with each of the two copies of gp130. The structural consequences of losing an exon lead to a unique pattern of lost interaction with different components of the receptor complex. Thus, in IL-6 and its splice variants, the exons appear to have compartmentalized roles contributing to the combined function of the cytokine. The modeled interactions suggest that splice variants could act as antagonists, and that IL-6delta2, missing the signal peptide, would be a cytoplasmic protein and be released and interact with nearby cell-surface receptors when cells are damaged. We argue that in the case of IL-6, helix E may act as a "silent secondary structure," which only has an active role when it substitutes for a part of the hydrophobic core, for example, replacing helix A in IL-6delta2.

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Interferons α/β and their receptors: place in the hierarchy of cytokines

Cited by 10 publications

References 215 publications

Thymosin α 1 activates dendritic cells for antifungal Th1 resistance through Toll-like receptor signaling

Thymosin α 1 activates dendritic cells for antifungal Th1 resistance through Toll-like receptor signaling

Interferon-Inducible Myxovirus Resistance Proteins: Potential Biomarkers for Differentiating Viral from Bacterial Infections

Negative modulation of signal transduction via interleukin splice variation

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