Host symptoms, such as aching muscles and fever, are related to the production of IFNs during infection. Interferons are also important in drug therapy for many diseases involving the immune system with extensive research being carried out on their use to treat diseases such as Multiple Sclerosis MS and Hepatitis. The mechanism of action by which interferons work is complex and advances in medicine and our understanding of the role of interferons will make a substantial impact on how diseases will be treated in the future.
Type I IFNs are typically produced by macrophages, neutrophils, dendritic cells and other somatic cells in response to many viruses and some pathogens. Founded by Dr. Recently, several excellent reviews describe the mechanism of nucleic acid sensing and signaling in the cytosol 34 — Within a period of hours, however, the signal decays and the STATs are exported back to the cytoplasm for the next round of signaling 38 , However, the other cytokines activate STAT homodimers that recognize different gamma-activated sequence.
Cellular responses to IFNAR ligation vary during the course of an immune response and are cell type-and context-dependent During PRR and inflammatory signaling, miR is highly induced 46 , Type-I and type-II IFNs are known to promote the expression of over 2, ISGs, and the products of ISGs have been shown to act by enhancing pathogen detection and innate immune signaling or restricting intracellular replication of viruses, bacteria, and parasites Activation of the inflammasome is a key event in inflammatory immune response.
The inflammasomes are cytosolic multiprotein complexes that are composed of an inflammasome-initiating sensor, apoptosis-associated speck-like protein containing a CARD ASC acts as an adaptor protein and the protease-caspase In addition, inflammasomes initiate pyroptotic cell death 52 , 57 , Pyroptosis involves cell swelling, membrane rupture, and release of the cytoplasmic content into the extracellular space 58 — Recently, several excellent reviews described mechanism of inflammasome activation 52 , 56 , 64 , Several NLR family members have been described as components of inflammasomes: Nlrp1b inflammasome 66 , 67 , Naip-Nlrc4 inflammasome 68 , 69 , the Nlrp6 inflammasome 70 , the Nlrp12 inflammasome, the Aim2 inflammasome 28 , 71 , the RIG-I inflammasome 72 , and the IFI16 inflammasome Particularly, the activation of Nlrp3 inflamamsome is well characterized 55 , 64 , 74 , Since it responds to variety of stimuli, many different mechanisms of its activation have been proposed, including the release of oxidized mitochondrial DNA, production of reactive oxygen species and mitochondrial dysfunction, lysosomal destabilization, changes in intracellular calcium levels, the formation of large non-specific membrane.
Moreover, Nlrp3 activation can be regulated through direct posttranslational modifications, such as ubiquitination Recently, several independent studies reported non-canonical inflammasome activation 78 — While canonical inflammasome activation results in caspase-1 cleavage and activation, the activation of a non-canonical inflammasome results in activation of procaspase The mouse caspase has high similarities to caspase-1 and is orthologous to human caspases-4 and -5 81 , Only caspasedeficient mice, but not caspasedeficient mice were partially protected from septic death 78 , Recent reports showed that caspase was involved in the response to cytosolic LPS, independently of TLR4 and was integral to the pathology of LPS-mediated endotoxic shock in mice Moreover, it was shown that human caspase-4 and caspase-5 and mouse caspase bound directly to LPS in the cytosol With the difference to canonical inflammasome activation were the receptor Nlrp3 and ASC form a scaffold on which caspase-1 can oligomerize, in non-canonical infalmmasome activation, caspase oligomerization occurs directly upon binding to LPS It was reported that canonical Nlrp3 inflammasome activation downstream of caspase-4 and caspase activation was dependent on potassium efflux 90 — Yang et al.
Inhibition of inflammasome activation by decoy proteins uses proteins structurally related to components of inflammasome and competing for the same adaptors. The CARD-only proteins and PYD-only proteins POPs function as endogenous dominant negative proteins that modulate the activity of inflammasomes and protect from excessive inflammation 94 , The genes encoding these decoy proteins, POPs, are located on the same chromosome, in the proximity of genes that encode their ligands: the gene encoding POP1 is located on human chromosome 16 next to the gene encoding ASC Interferons could contribute to inflammasome activation through several different mechanisms Figure 1.
It was reported that type I IFNs are required for the caspase expression, which contributes to activation of non-canonical inflammasome Several recent studies have shown that IFN-inducible endogenous proteins could act also as negative regulators and thus inhibit inflammasome activation 97 , Among others, interferon-inducible GBPs not only mediate host resistance to pathogens but also promote inflammasome activation in bacterial infections , Not only POPs but also metabolites like hydroxycholesterol, an oxysterol and is derived from cholesterol, suppress inflammasome activation Work of Reboldi et al.
The authors proposed that hydroxycholesterol antagonized the sterol response element-binding protein processing Moreover, cholesterol hydroxylase-deficient mice showed increased sensitivity to LPS-induced septic shock Figure 1. Type I interferons IFNs and inflammasome activation. Active caspase-1 and caspase cleave GSDMD and the released gasdermin-N domain binds to phosphoinositides in the plasma membrane, oligomerizes to generate membrane pores, and initiates cell death-pyroptosis.
NO plays an important role in a defense against pathogens, it could be oxidized to reactive nitrogen oxide species, that S -nitrosate thiols in proteins 15 , Mishra et al. Also study by Mao et al. Guarda et al. In addition, they demonstrated that the recruitment of inflammatory cells neutrophils and monocytes into peritoneal cavity was significantly lower in poly I:C pretreated mice, than in control animals injected only with LPS.
Several recent studies reported cross talk between IFNs and inflammasome activation in bacterial infections 79 , , , , Rathinam et al. Gurung et al. Aachoui et al. Oficjalska et al. GBPs have also been shown to regulate the entry of LPS into the cytosol by, as yet, poorly defined mechanisms However, studies on different mouse strain of GBP5 - deficient mice could not confirm the initial results , Despite the uncertainty surrounding the role of GBP5 in Nlrp3 inflammasome activation, studies using mice lacking the entire cluster of GBP genes on chromosome 3, have firmly confirmed a functional link between GBPs and the activation of the canonical NLRP3 and AIM2 inflammasomes, as well as the non-canonical caspase inflammasomes.
Figure 2. ZBP1-deficient mice were protected from mortality during IAV infection, due to reduced inflammatory response I have summarized considerable, but by no means all evidence documenting the role of IFNs in inflammasome activation and inflammation. Several recent studies reported the essential role of type I IFNs in non-canonical Nlrp3 inflammasome activation and pyroptosis.
Different levels of regulation are involved in the cross talk of IFNs in inflammasome. Dysregulated type I-IFN production could lead to a cell death. However, a recent study reported that in the absence of active proapoptotic caspases-3 and -7, mitochondrial outer membrane permeabilization by Bax and Bak resulted in the expression of type I-IFNs.
Particularly, the role of STAT and other protein modification in IFN signaling pathways could give us important insight into the regulatory mechanisms. IFN-induced GBPs were reported to have an important role in caspase activation and pyroptotic cell death.
How does the polymorphisms of GBPs influence inflammasome activation and inflammation is yet to be determined. Future research should explore the detailed molecular mechanisms that are responsible for type I IFN-dependent cell death and inflammasome activation in inflammatory response. Moreover, recently, several studies determined the role of cytokines in metabolic reprograming and inflammasome activation The role cross talk of IFNs, inflammasomes, and metabolism could be a future frontier for the cutting edge research.
Identification of the factors involved in inflammasome regulation and signaling will lead to the identification of novel targets for therapeutic intervention. The author confirms being the sole contributor of this work and approved it for publication. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author acknowledges the financial support from the Slovenian Research Agency research core funding No.
Medzhitov R. Inflammation new adventures of an old flame. Cell —6. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol — Origin and physiological roles of inflammation. Nature — Pathogen recognition and innate immunity. Cell — Recognition of microorganisms and activation of the immune response. Toll-like receptors. Curr Biol Sensing and reacting to microbes through the inflammasomes. Nat Immunol — Takeuchi O, Akira S. Pattern recognition receptors and inflammation.
Immune sensing of DNA. Immunity — Isaacs A, Lindenmann J. Virus interference. The interferon. Regulation of type i interferon responses. Type I interferons in infectious disease. The interferons and their receptors — distribution and regulation. Immunol Cell Biol — The cellular inhibitor of the PKR protein kinase, P58 IPK , is an influenza virus-activated co-chaperone that modulates heat-shock protein 70 activity. Polyak, S. The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity.
Wang, X. Geiss, G. Cellular transcriptional profiling in influenza virus-infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza.
This study examined the effects of NS1 protein expression during influenza A virus infection on global cellular mRNA levels using high-density microarrays. It indicated that the cellular IFN response to influenza A virus infection in lung epithelial cells is influenced markedly by the sequence of the NS1 gene, and it characterized a virus that contains the pandemic influenza NS1 gene.
Krebs, D. SOCS proteins: negative regulators of cytokine signaling. Stem Cells 19 , — He, Y. To interfere and to anti-interfere: the interplay between hepatitis C virus and interferon. Viral Immunol. Tan, S. How hepatitis C virus counteracts the interferon response: the jury is still out on NS5A. Virology , 1—12 Taylor, D.
Hepatitis C virus and interferon resistance: it's more than just PKR. Hepatology 33 , — Bartenschlager, R. Novel cell-culture systems for the hepatitis C virus. Antiviral Res. Molecular clones of hepatitis C virus: applications to animal models. ILAR J. PubMed Article Google Scholar. Pawlotsky, J. Hepatitis C virus resistance to antiviral therapy. Hepatology 32 , — Bukh, J. Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Liver Dis. Enomoto, N.
Comparison of full-length sequences of interferon-sensitive and -resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino-acid substitutions in the NS5A region. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. Nakano, I. Witherell, G. Statistical analysis of combined substitutions in nonstructural 5A region of hepatitis C virus and interferon response.
Lohmann, V. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science , — Blight, K. Frese, M. Guo, J. Sumpter, R. Whitley, R. USA 97 , — Roizman, B. Ankel, H. Kumar-Sinha, C. Preston, C. Activation of interferon response factor-3 in human cells infected with herpes simplex virus type 1 or human cytomegalovirus. Eidson, K. Expression of herpes simplex virus ICP0 inhibits the induction of interferon-stimulated genes by viral infection.
Mossman, K. Harle, P. Jr, Carr, D. He, B. USA 94 , — Cassady, K. The herpes simplex virus type 1 U S 11 protein interacts with protein kinase R in infected cells and requires a amino-acid sequence adjacent to a kinase substrate domain. Leib, D. Specific phenotypic restoration of an attenuated virus by knockout of a host resistance gene. Using recombinant viruses to infect animals that have null mutations in host-defence genes, this study showed that a virus that was attenuated by deletion of ICP Poppers, J.
Esposito, J. Moss, B. Cohen, J. Smallpox vaccinations: how much protection remains? Science , Smith, G. Smallpox: anything to declare? Nature Rev. Alcami, A. Trends Microbiol. McFadden, G. Host-related immunomodulators encoded by poxviruses and herpesviruses. Lalani, A. Use of chemokine receptors by poxviruses. Cytokine receptors encoded by poxviruses: a lesson in cytokine biology. Today 16 , — Virus-encoded receptors for cytokines and chemokines.
Cell Dev. Colamonici, O. Symons, J. Vaccinia virus encodes a soluble type I interferon receptor of novel structure and broad species specificity. Cell 81 , — This study characterized the vaccinia-virus soluble type I IFN receptor encoded by the B18R gene, which has broad species specificity and might have aided vaccinia-virus replication in many host species during evolution.
Verardi, P. Sroller, V. Akkaraju, G. Vaccinia-specific kinase inhibitory factor prevents translational inhibition by double-stranded RNA in rabbit reticulocyte lysate. Watson, J. Characterization of a vaccinia virus-encoded double-stranded RNA-binding protein that may be involved in inhibition of the double-stranded RNA-dependent protein kinase. Chang, H. The E3L gene of vaccinia virus encodes an inhibitor of the interferon-induced, double-stranded RNA-dependent protein kinase.
USA 89 , — Beattie, E. Davies, M. Massung, R. Analysis of the complete genome of smallpox variola major virus strain Bangladesh Shchelkunov, S. Comparison of the genetic maps of variola and vaccinia viruses. FEBS Lett. The E3L and K3L vaccinia virus gene products stimulate translation through inhibition of the double-stranded RNA-dependent protein kinase by different mechanisms.
Sharp, T. Carroll, K. Rivas, C. Smith, E. Liu, Y. Vaccinia virus E3L interferon resistance protein inhibits the interferon-induced adenosine deaminase A-to-I editing activity. Brandt, T. Both carboxy- and amino-terminal domains of the vaccinia virus interferon resistance gene, E3L , are required for pathogenesis in a mouse model. Najarro, P. Cummings, C. Using DNA microarrays to study host—microbe interactions.
Fruh, K. Virogenomics: a novel approach to antiviral drug discovery. Drug Discov. Today 6 , — Manger, I. How the host 'sees' pathogens: global gene expression responses to infection. Dongre, A. Proteomics in the post-genome age. Biopolymers 60 , — Uetz, P. A comprehensive analysis of protein—protein interactions in Saccharomyces cerevisiae. Nature , — Kellam, P. Post-genomic virology: the impact of bioinformatics, microarrays and proteomics on investigating host and pathogen interactions.
Ideker, T. A new approach to decoding life: systems biology. Genomics Hum. Integrated genomic and proteomic analyses of a systematically perturbed metabolic network. Simmen, K. Global modulation of cellular transcription by human cytomegalovirus is initiated by viral glycoprotein B. USA 98 , — Using high-density microarrays, this study identified the specific viral component that triggers the cellular IFN response as the envelope glycoprotein B gB , highlighting a pioneering paradigm for the consequences of virus—receptor interactions.
Herpes simplex virus triggers and then disarms a host antiviral response. Global impact of influenza virus on cellular pathways is mediated by both replication-dependent and -independent events. A comprehensive view of regulation of gene expression by double-stranded RNA-mediated cell signaling. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation.
Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Noguchi, T. Effects of mutation in hepatitis C virus nonstructural protein 5A on interferon resistance mediated by inhibition of PKR kinase activity in mammalian cells. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response.
Girard, S. An altered cellular response to interferon and up-regulation of interleukin-8 induced by the hepatitis C viral protein NS5A uncovered by microarray analysis. Bigger, C. DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection.
Toshchakov, V. Nature Immunol. This study highlighted the cross-talk between TLRs and IFN — two pivotal host anti-microbial pathways — and provided the first explanation for the mechanistic basis of the differential patterns of gene expression that are activated by different TLR agonists.
Mita, Y. Miettinen, M. IFNs activate toll-like receptor gene expression in viral infections. Genes Immun. Aderem, A. Toll-like receptors in the induction of the innate immune response. Alexopoulou, L. It was also found that TLR3-deficient mice have reduced responses to poly inosine:cytosine. Interferon action in triply deficient mice reveals the existence of alternative antiviral pathways. Horng, T. O'Shea, J. Cell , S—S Aaronson, D. Heim, M. Signal Transduct. Yeh, T. The Janus kinase family of protein tyrosine kinases and their role in signaling.
Meraz, M. Cell 84 , — This study generated and characterized Stat1-deficient mice, which have a complete lack of response to IFNs and are highly sensitive to microbial and viral infection, showing that STAT1 has an obligate and dedicated role in mediating IFN-dependent biological responses. Cox, N.
0コメント