STAT-1α and IFN-γ as Modulators of TNF-α Signaling in Macrophages: Regulation and Functional Implications of the TNF Receptor 1:STAT-1α Complex

Wesemann, Duane R.; Benveniste, Etty N.

doi:10.4049/jimmunol.171.10.5313

Cited by 73 publications

(63 citation statements)

References 21 publications

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“…This hypothesis arises chief ly from work done by using TRADD knockdown in RAW cells, which showed that signaling in response to IFN␥ stimulation increased in the absence of TRADD (25). However, our investigation does not support a negative regulatory role for TRADD in IFN␥-induced responses.…”

Section: Discussioncontrasting

confidence: 49%

Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors

Chen

Chio

Lin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

103

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Tumor necrosis factor receptor 1-associated death domain protein (TRADD) is the core adaptor recruited to TNF receptor 1 (TNFR1) upon TNF␣ stimulation. In cells from TRADD-deficient mice, TNF␣-mediated apoptosis and TNF␣-stimulated NF-B, JNK, and ERK activation are defective. TRADD is also important for germinal center formation, DR3-mediated costimulation of T cells, and TNF␣-mediated inflammatory responses in vivo. TRADD deficiency does not enhance IFN␥-induced signaling. Importantly, TRADD has a novel role in TLR3 and TLR4 signaling. TRADD participates in the TLR4 complex formed upon LPS stimulation, and TRADD-deficient macrophages show impaired cytokine production in response to TLR ligands in vitro. Thus, TRADD is a multifunctional protein crucial both for TNFR1 signaling and other signaling pathways relevant to immune responses. TNF ͉ innate immunityT umor necrosis factor alpha (TNF␣) is a pleiotropic cytokine involved in a broad range of biological activities, including inflammation and cell differentiation, survival, and death (1). TNF␣ mediates these activities by engaging two distinct cell surface receptors: TNFR1 and TNFR2. Activation of TNFR1 leads to the recruitment of the intracellular death domain (DD)-containing adaptor TNFR-associated DD protein (TRADD) through a homotypic interaction with DD of TNFR1. On one hand, the recruitment of TRADD can promote the association of the TNFR1 complex with Fas-associated DD (FADD), which induces caspase activation and cell death. On the other hand, TRADD can also recruit receptor-interacting protein kinase 1 (RIP1) and TNFR-associated factor-2 (TRAF2), which trigger NF-B activation, leading to cell survival and proinflammatory responses (1).TRADD was originally identified in a yeast two-hybrid screen performed to identify TNFR1-interacting proteins (2). Intriguingly, TRADD is the first adaptor protein identified that binds directly to the DD of TNFR1 but transduces signals resulting in either apoptosis or NF-B activation (2-4). Indeed, TRADD overexpression in 293T cells activates both apoptotic and cellsurvival signaling pathways (2). In addition to TNFR1, TRADD may mediate signaling downstream of the death receptors (and TNFR superfamily members) DR3 and DR6 (5, 6). As well, recent TRADD knockdown studies have indicated that TRADD may be involved in signaling mediated by receptors unrelated to the TNFR superfamily, such as in IFN␥ receptor (7-9). These findings give tantalizing hints of the potential breadth of TRADD functions.To date, a knockout animal model has yet to be reported for TRADD, even though this important adaptor was identified more than ten years ago. In this study, we generate TRADD knockout mice by using conditional gene targeting and show that not only is TRADD indispensable for TNF␣-induced NF-B activation and apoptosis in vitro and TNF␣-induced inflammatory responses in vivo, but also that this molecule is involved in germinal center (GC) formation, T cell costimulation, and TLR signaling. Our TRADD knockout mice represent a very useful t...

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Section: Discussioncontrasting

confidence: 49%

Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors

Chen

Chio

Lin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

103

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“…While Jak activation was necessary for protection of cells from TNFα, STAT1 protein was necessary for TNFα to act as a cell death signal (consistent with previous studies in a macrophage cell line where non-phosphorylated STAT1 interacts with the TNF receptor (TNFR1) leading to caspase activity and subsequent apoptosis 28 ). Analysis of cell death after 3d showed that knockdown of STAT1 by short hairpin RNA (shRNA) itself prevented TNFα-induced oligodendrocyte death, as compared to scrambled control-treated cells (Figures 3d and f).…”

Section: Resultssupporting

confidence: 68%

cFLIP is critical for oligodendrocyte protection from inflammation

et al. 2015

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Neuroinflammation associated with degenerative central nervous system disease and injury frequently results in oligodendrocyte death. While promoting oligodendrocyte viability is a major therapeutic goal, little is known about protective signaling strategies. We report that in highly purified rat oligodendrocytes, interferon gamma (IFNγ) activates a signaling pathway that protects these cells from tumor necrosis factor alpha (TNFα)-induced cytotoxicity. IFNγ protection requires Jak (Janus kinase) activation, components of the integrated stress response and NF-κB activation. Although NF-κB activation also occurred transiently in the absence of IFNγ and presence of TNFα, this activation was not sufficient to prevent induction of the TNFα-responsive cell death pathway. Genetic inhibition of NF-κB translocation to the nucleus abrogated IFNγ-mediated protection and did not change the cell death induced by TNFα, suggesting that NF-κB activation via IFNγ induces a different set of responses than activation of NF-κB via TNFα. A promising candidate is the NF-κB target cFLIP (cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein), which is protease-deficient caspase homolog that inhibits caspase-3 activation. We show that IFNγ-mediated protection led to upregulation of cFLIP. Overexpression of cFLIP was sufficient for oligodendrocyte protection from TNFα and short hairpin RNA knockdown of cFLIP-abrogated IFNγ -mediated protection. To determine the relevance of our in vitro finding to the more complex in vivo situation, we determined the impact on oligodendrocyte death of regional cFLIP loss of function in a murine model of neuroinflammation. Our data show that downregulation of cFLIP during inflammation leads to death of oligodendrocytes and decrease of myelin in vivo. Taken together, we show that IFNγ-mediated induction of cFLIP expression provides a new mechanism by which this cytokine can protect oligodendrocytes from TNFα-induced cell death.

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“…RIPK1 kinase activity modulates signaling downstream of TNF-R. As TNFα signaling following receptor engagement involves activation (phosphorylation) of STAT1, [25][26][27] we measured pS727-STAT1 levels following LPS/zVAD or TNFα/zVAD treatment of macrophages. Phosphorylation of STAT1 was reduced in RIPK1 K45A macrophages following LPS/zVAD treatment (Figures 3a and b Furthermore, TNF-R signaling also initiates a rapid and transient induction of c-Jun N-terminal kinase (JNK).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the K45A mutation of RIPK1 significantly impacted cytokine signaling as revealed by poor p-STAT1 phosphorylation at S727 during necroptotic stimulation, which in turn may reflect the reduction in caspase activity. Phosphorylation of STAT1 at Y701 is required to decouple the STAT1 from TNF-R, 26 but phosphorylation at S727 is required for maximal STAT1-dependent gene transcription. 25 Our results indicate an impairment in chemokine expression in RIPK1 kinase-dead macrophages, which correlated with S727-STAT1 phosphorylation.…”

Section: Ripk1 Interacts With Various Proteins Such As Ciaps Andmentioning

confidence: 99%

K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo

et al. 2016

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Receptor interacting protein kinase 1 (RIPK1) participates in several cell signaling complexes that promote cell activation and cell death. Stimulation of RIPK1 in the absence of caspase signaling induces regulated necrosis (necroptosis), which promotes an inflammatory response. Understanding of the mechanisms through which RIPK1 promotes inflammation has been unclear. Herein we have evaluated the impact of a K45A mutation of RIPK1 on necroptosis of macrophages and the activation of inflammatory response. We show that K45A mutation of RIPK1 results in attenuated necroptosis of macrophages in response to stimulation with LPS, TNFα and IFNβ in the absence of caspase signaling. Impairment in necroptosis correlated with poor phosphorylation of RIPK1, RIPK3 and reduced trimerization of MLKL. Furthermore, K45A mutation of RIPK1 resulted in poor STAT1 phosphorylation (at S727) and expression of RANTES and MIP-1α following TNF-R engagement in the absence of caspase activation. Our results further indicate that in the absence of stimulation by pathogen-associated molecular patterns (PAMPs), cellular inhibitors of apoptotic proteins (cIAPs) prevent the K45-dependent auto-phosphorylation of RIPK1, leading to resistance against necroptosis. Finally, RIPK1K45A mice displayed attenuated inflammatory response in vivo as they were significantly resistant against endotoxin shock, but highly susceptible against a challenge with Salmonella typhimurium. This correlated with reduced expression of IL-1β and ROS, and poor processing of caspase 8 by RIPK1K45A macrophages. Overall, these results indicate that K45 mediated kinase activity of RIPK1 is not only important for necroptosis but it also has a key role in promoting cytokine signaling and host response to inflammatory stimuli. Apoptosis is considered as the predominant, programmed pathway of cell death; however, recently several pathways of regulated cell death have been shown to operate in cells that are considered highly inflammatory.1,2 Although apoptosis has a major role during fetal development, 3 regulated necrotic cell death does not appear to influence fetal development. 4 Interestingly, receptor interacting protein kinase 1 (RIPK1) deficiency cause embryonic lethality, suggesting a key role of RIPK1 in host survival. 5 Besides the kinase activity, RIPK1 appears to have a scaffolding function, which may influence immune homeostasis. 6,7 Depending on the interacting partners and posttranslational modifications, RIPK1 has a multifaceted role in cell signaling and cell survival.8 Following TNF-R1 signaling, RIPK1 transitions between pro-survival and pro-cell death signaling complexes. 9,10 Necroptosis is a form of regulated necrosis of cells that operates in the absence of caspase activity 9 and is initiated by the engagement of various TLRs or cytokine receptors.11 The first cardinal signaling step in necrosome signaling is the phosphorylation of RIPK1, which leads to RIPK1-RIPK3 interaction and phosphorylation of RIPK3.12 Although necroptotic signaling has been shown to be...

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STAT-1α and IFN-γ as Modulators of TNF-α Signaling in Macrophages: Regulation and Functional Implications of the TNF Receptor 1:STAT-1α Complex

Cited by 73 publications

References 21 publications

Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors

Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors

cFLIP is critical for oligodendrocyte protection from inflammation

K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo

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