Cytokine synergy: An underappreciated contributor to innate anti-viral immunity

Bartee, Eric; McFadden, Grant

doi:10.1016/j.cyto.2013.04.036

Cited by 56 publications

(50 citation statements)

References 40 publications

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“…As RNA expression of the signaling intermediary Myd88, a fundamental component of the TLR signaling pathway, 51,52 was, like STAT1, attenuated in cells lacking constitutive IFNb signaling, it is plausible that tonic IFNa/ b augments TLR responsiveness by regulating the expression of Myd88. Moreover, as expression or activation of transcription factors involved in signaling via other cytokines known to engage in crosstalk with IFNa/b such as IL-6, IL-1 and TNFa 6,27,28,[53][54][55] were also revealed by our studies to be attenuated in IFNAR1-deficient cells, it suggest that tonic IFNa/b also regulates responsiveness to these cytokines by this mechanism.…”

Section: Discussionmentioning

confidence: 74%

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Constitutive IFNα/β signaling maintains expression of signaling intermediaries for efficient cytokine responses

2016

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Interferons (IFNs) are a family of immunoregulatory cytokines with important roles in anti-viral and anti-tumor responses. Type I and II IFNs bind distinct receptors and are associated with different stages of the immune response. There is however, considerable crosstalk between these two cytokines with enhancement of IFNγ responses following IFNα/β priming and loss of IFNα/β receptor (IFNAR) resulting in diminished IFNγ responses. In this study, we sought to define the mechanism of crosstalk between the type I and II IFNs. Our previous reports demonstrated reduced expression of the canonically activated transcription factor signal transducer and activator of transcription (STAT)1, in cells lacking the IFNAR α chain (IFNAR1). Therefore, we used microarray analysis to determine whether reconstitution of STAT1 in IFNAR1-deficient cells was sufficient to restore IFNγ responses. We identified several biological pathways, including the MHC class I antigen presentation pathway, in which STAT1 reconstitution was able to significantly rescue IFNγ-mediated gene regulation in Ifnar1 (-/-) cells. Notably, we also found that in addition to low basal expression of STAT1, cells lacking the IFNAR1 also had aberrant expression of multiple other transcription factors and signaling intermediaries. The studies described herein demonstrate that basal and regulated expression of signaling intermediaries is a mechanism for crosstalk between cytokines including type I and II IFNs.

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Section: Discussionmentioning

confidence: 74%

“…In contrast, the physiological scenario of concomitant exposure to several cytokines and the consequences and mechanisms regulating these interactions are relatively undefined. 28 Cytokine crosstalk can occur at the level of the receptor, by regulation of the expression of receptor components or the e1173804- 8 Messina et al…”

Section: Discussionmentioning

confidence: 99%

Constitutive IFNα/β signaling maintains expression of signaling intermediaries for efficient cytokine responses

2016

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“…While TNFα is reported to potentiate the antiviral effects of IFNs against an array of DNA and RNA viruses 15, 17, 38 , the mechanisms behind such activities are not well understood. It has been proposed that TNFα acts in part by inducing expression of IFNβ in some cell types (reviewed in 38 ).…”

Section: Discussionmentioning

confidence: 99%

“…TNFα can mediate antiviral activities by itself 15, 16 and in synergy with IFNs (reviewed in 17 ). In hepatocytes, TNFα was reported to inhibit hepatitis B virus (HBV) gene expression and replication, and to synergize with IFNγ 18–20 .…”

Section: Introductionmentioning

confidence: 99%

Tumor Necrosis Factor Inhibits Spread of Hepatitis C Virus Among Liver Cells, Independent From Interferons

et al. 2017

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Background & Aims Tumor necrosis factor (TNF) an inflammatory cytokine expressed by human fetal liver cells (HFLCs) following infection with cell culture-derived hepatitis C virus. TNF has been reported to increase entry of HCV pseudoparticles into hepatoma cells and inhibit signaling by interferon alpha (IFNA), but have no effect on replication of HCV RNA. We investigated the effects of TNF on HCV infection of and spread among Huh-7 hepatoma cells and primary HFLCs. Methods Human hepatoma (Huh-7 and Huh-7.5) and primary HFLCs were incubated with TNF and/or recombinant IFNA2A, IFNB, IFNL1, and IFNL2 before or during HCV infection. We used 2 fully infectious HCV chimeric viruses of genotype 2A in these studies: J6/JFH (Clone 2) and Jc1(p7-nsGluc2A) (Jc1G), which encodes a secreted luciferase reporter. We measured HCV replication, entry, spread, production, and release in hepatoma cells and HFLCs. Results TNF inhibited completion of the HCV infectious cycle in hepatoma cells and HFLC in a dose-dependent and time-dependent manner. This inhibition required TNF binding to its receptor. Inhibition was independent of IFNA, IFNB, IFNL1, IFNL2, or JAK signaling via STAT. TNF reduced production of infectious viral particles by Huh-7 and HFLC, and thereby reduced numbers of infected cells and size of foci. TNF had little effect on HCV replicons and increased entry of HCV pseudoparticles. When cells were incubated with TNF before infection, the subsequent anti-viral effects of IFNs were increased. Conclusion In a cell culture system, we found TNF to have antiviral effects independently of, as well as in combination with, IFNs. TNF inhibits HCV infection despite increased HCV envelope glycoprotein-mediated infection of liver cells. These findings contradict those from other studies, which reported that TNF blocks signal transduction in response to IFNs. The destructive inflammatory effects of TNF must be considered along with its antiviral effects.

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“…Since then, intensive research efforts have been focused on key cytokines such as IL-1, IL-6, IL-12 and IL-17 and the targeting of these molecules therapeutically in a variety of inflammatory and autoimmune diseases [15,48]. It is being increasingly recognized that cytokines do not act in isolation, but function within a milieu of multiple cytokines with the ability to synergize with or antagonize one another's functional capacity [47,51]. For example, in-vitro studies examining the combined effects of TNF-α, IL-1β and IL-17 demonstrated enhanced activation of inflammatory signalling pathways in comparison to the individual cytokines alone.…”

Section: Current Concepts In Cytokine Functioningmentioning

confidence: 99%

Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications

Moran

Mastaglia

2014

Clinical and Experimental Immunology

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SummaryThe idiopathic inflammatory myopathies are a heterogeneous group of disorders characterised by diffuse muscle weakness and inflammation. A common immunopathogenic mechanism is the cytokine-driven infiltration of immune cells into the muscle tissue. Recent studies have further dissected the inflammatory cell types and associated cytokines involved in the immune-mediated myopathies and other chronic inflammatory and autoimmune disorders. In this review we outline the current knowledge of cytokine expression profiles and cellular sources in the major forms of inflammatory myopathy and detail the known mechanistic functions of these cytokines in the context of inflammatory myositis. Furthermore, we discuss how the application of this knowledge may lead to new therapeutic strategies for the treatment of the inflammatory myopathies, in particular for cases resistant to conventional forms of therapy.

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Cytokine synergy: An underappreciated contributor to innate anti-viral immunity

Cited by 56 publications

References 40 publications

Constitutive IFNα/β signaling maintains expression of signaling intermediaries for efficient cytokine responses

Constitutive IFNα/β signaling maintains expression of signaling intermediaries for efficient cytokine responses

Tumor Necrosis Factor Inhibits Spread of Hepatitis C Virus Among Liver Cells, Independent From Interferons

Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications

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