Physiological levels of TNFα stimulation induce stochastic dynamics of NF-κB responses in single living cells

Turner, David A.; Paszek, Pawel; Woodcock, Dan J.; Nelson, David E.; Horton, Caroline A.; Wang, Yunjiao; Spiller, David G.; Rand, D.A.J.; White, Mike; Harper, Claire V.

doi:10.1242/jcs.069641

Cited by 102 publications

(128 citation statements)

References 39 publications

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“…The amount of IL-6 mRNA was increased by IFN-g slightly, although the increase was not statistically significant. Previous studies suggested that the physiological levels of TNF-a are much lower than those that we use in in vitro experiments (10 ng/ml) (39,40). Thus, we stimulated cpdm MEFs with 0.1 ng/ml TNF-a and found that IFN-g pretreatment did not increase the amount of TNF-a and VCAM-1 mRNA, although it significantly induced IL-6 mRNA (Fig.…”

Section: Ifn-g Suppresses Apoptosis But Does Not Effectively Augment mentioning

confidence: 62%

IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex

Tamiya

Terao

Takiuchi

et al. 2014

The Journal of Immunology

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The linear ubiquitin chain assembly complex (LUBAC) ubiquitin ligase complex, composed of HOIL-1L–interacting protein (HOIP), heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), and SHANK-associated RH domain protein, specifically generates linear polyubiquitin chains and is involved in NF-κB activation. Lack of SHANK-associated RH domain protein, which drastically reduces the amount of HOIP and HOIL-1L, causes chronic proliferative dermatitis (cpdm) in mice. Impaired NF-κB activation and augmented apoptosis have been implicated in the pathogenesis of cpdm in mice. In this study, we found that IFN-γ increased the amount of LUBAC by inducing HOIP and HOIL-1L mRNA transcription and enhanced the signal-induced NF-κB activation in embryonic fibroblasts, keratinocytes, and bone marrow–derived macrophages from wild-type and/or cpdm mice; however, IFN-γ failed to augment NF-κB activation in mouse embryonic fibroblasts lacking linear polyubiquitination activity of LUBAC. Moreover, s.c. injection of IFN-γ for 3 wk into the skin of cpdm mice increased the amount of HOIP, suppressed apoptosis, and ameliorated the dermatitis. Inhibition of keratinocyte apoptosis by IFN-γ injection suppressed neutrophil, macrophage, and mast cell infiltration and the amount of TNF-α in the skin of cpdm mice. Similarly, IFN-α also enhanced the amount of HOIP as well as NF-κB activation, inhibited apoptosis, and ameliorated cpdm dermatitis. These results indicate that the IFNs enhance NF-κB activation and ameliorate cpdm dermatitis by augmenting expression of HOIP and HOIL-1L and linear polyubiquitination activity of LUBAC.

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Section: Ifn-g Suppresses Apoptosis But Does Not Effectively Augment mentioning

confidence: 62%

IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex

Tamiya

Terao

Takiuchi

et al. 2014

The Journal of Immunology

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“…3T3 cell lysates were used as reference controls. Experiments were performed at this dose, as the physiological (15 pg/ml) and pathogenic (5 ng/ml) levels of TNF-a did not elicit measurable changes in many in vitro experimental studies 32 Figure 1c) were unaffected at the physiological and pathogenic doses of TNF-a. Cell viability based on trypan blue dye exclusion further revealed high mortality in granulocytes treated with 50 ng/ml TNF-a at 4 and 24 h. In contrast, mortality was low in granulocytes treated with doses less than 50 ng/ml at all time points (Supplementary Table I).…”

Section: Resultsmentioning

confidence: 99%

SOCS3 dictates the transition of divergent time-phased events in granulocyte TNF-α signaling

2013

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Tumor-necrosis factor-a (TNF-a)-driven nuclear factor-kB (NF-kB) activation and apoptosis are opposing pathways; the growing recognition of these conflicting roles of TNF-a is perplexing. Here, we show that inflammation and apoptosis are time-phased events following TNF-a signaling and that emergence of suppressor of cytokine signaling 3 (SOCS3) expression limits the ongoing NF-kB activation and promotes apoptosis; further, we suggest an altered view of how inflammatory diseases are initiated and sustained. In vitro, TNF-a (50 ng/ml) induced granulocyte SOCS3 protein, inhibited nuclear accumulation of the p65NF-kB subunit and enhanced apoptosis, as shown by DNA laddering, annexin V positivity, and overexpression of caspase-3 and Bax in the late phase, whereas the early phase was marked by NF-kB activation. Conversely, SOCS3 knockdown by small interfering RNA (siRNA) inhibited granulocyte apoptosis and enhanced nuclear accumulation of p65 and 59 lipooxygenase expression in the late phase of TNF-a signaling. As apoptosis is associated with SOCS3 abundance, we suggest that these divergent TNF-a-driven events are time-phased, interconnected, opposing control mechanisms and one of the central features through which the immune system resolves pulmonary inflammation. Dysregulation may initiate mucosal inflammation, thus changing the landscape of asthma therapy.

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“…Both Tay et al and Turner et al have shown that not all cells respond to low concentrations of TNFα, and that this is probably due to a heterogonous digital process. IKK (the inhibitor of IκB) needs multiple phosphorylation steps to become activated, which could lead to a digital cellular response profile [43,44].…”

Section: Modelingmentioning

confidence: 99%

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

Kuijper

Yang

Water

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed in drug-induced liver injury. Dynamical pathway modeling has the potential to foresee adverse effects of drugs before they go in trial. Ordinary differential equation modeling can offer mechanistic insight, and allows us to study the dynamical behavior of stress pathways involved in DILI. Areas covered: This review provides an overview on the progress of the dynamical modeling of stress and death pathways pertinent to DILI, i.e. pathways relevant for oxidative stress, inflammatory stress, DNA damage, unfolded proteins, heat shock and apoptosis. We also discuss the required steps for applying such modeling to the liver. Expert opinion: Despite the strong progress made since the turn of the century, models of stress pathways have only rarely been specifically applied to describe pathway dynamics for DILI. We argue that with minor changes, in some cases only to parameter values, many of these models can be repurposed for application in DILI research. Combining both dynamical models with in vitro testing might offer novel screening methods for the harmful side-effects of drugs. ARTICLE HISTORY

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Physiological levels of TNFα stimulation induce stochastic dynamics of NF-κB responses in single living cells

Cited by 102 publications

References 39 publications

IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex

IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex

SOCS3 dictates the transition of divergent time-phased events in granulocyte TNF-α signaling

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

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