Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF-α and PGE2

Hu, Yang; Park‐Min, Kyung‐Hyun; Yarilina, Anna; Ivashkiv, Lionel B.

doi:10.1189/jlb.0107040

Cited by 26 publications

(22 citation statements)

References 43 publications

(81 reference statements)

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“…IFN-b can be triggered by additional stimuli such as cytosolic microbial DNA (50,51). Notably, also TNF itself has recently been found to trigger a partial IFN response in Mo-DCs or even a release of type I IFN in macrophages, although counterregulation has been observed as well, at least in plasmacytoid DCs (52)(53)(54). The net effect of TNF on DC apoptosis in our experiments, in any case, was clearly protective.…”

Section: Discussionmentioning

confidence: 57%

Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

Lehner

Kellert

Proff

et al. 2012

The Journal of Immunology

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The life span of dendritic cells (DCs) is determined by the balance of pro- and antiapoptotic proteins. In this study, we report that serum-free cultured human monocyte-derived DCs after TLR stimulation with polyinosinic acid-polycytidylic acid or LPS underwent apoptosis, which was correlated with low TNF production. Apoptosis was prevented by the addition of exogenous TNF or by concomitant stimulation with R-848, which strongly amplified endogenous TNF production. Neutralization of TNF confirmed that DC survival was mediated by autocrine TNF induced either by stimulation with R-848 or by ligation of CD40. DCs stimulated by polyinosinic acid-polycytidylic acid or IFN-β, another known inducer of DC apoptosis, were characterized by high levels and activation of the proapoptotic protein BAK. The ratio of antiapoptotic BCL-2 to BAK correlated best with the survival of activated DCs. Addition of TNF increased this ratio but had little effect on BAX and XIAP. Knockdown experiments using small interfering RNAs confirmed that the survival of activated and also of immature DCs was regulated by BAK and showed that TNF was protective only in the presence of FLIPL. Together, our data demonstrate that the survival of DCs during differentiation and activation depends on autocrine TNF and that the inhibition of BAK plays an important role in this process.

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Section: Discussionmentioning

confidence: 57%

Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

Lehner

Kellert

Proff

et al. 2012

The Journal of Immunology

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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%

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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“…IFN-γ antagonizes the effect of STAT3 by activating STAT1 and SOCS3 [ 32 , 33 ]. TNF-α promotes STAT1 activation by increasing serine phosphorylation of STAT1 [ 34 ], and also negatively modulates the effect of STAT3 by activating PI3K pathway [ 35 , 36 ]. Nevertheless, it has been unclear whether IFN-γ and TNF-α are able to modulate the response of G-CSF/IL-6-primed neutrophils to T-sMs.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils with protumor potential could efficiently suppress tumor growth after cytokine priming and in presence of normal NK cells

et al. 2014

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In tumor-bearing state, the function of neutrophils is converted from tumor-suppressing to tumor-promoting. Here we report that priming with IFN-γ and TNF-α could convert the potential of neutrophils from tumor-promoting to tumor-suppressing. The neutrophils with protumor potential have not lost their responsiveness to IFN-γ and TNF-α. After priming with IFN-γ and TNF-α, the potential of the neutrophils to express Bv8 and Mmp9 genes was reduced. Conversely, the tumor-promotional neutrophils recovered the expression of Rab27a and Trail, resumed the activation levels of PI3K and p38 MAPK pathways in response to stimuli, and expressed higher levels of IL-18 and NK-activating ligands such as RAE-1, MULT-1, and H60. Therefore, the anti-tumor function of the neutrophils was augmented, including the cytotoxicity to tumor cells, the capability of degranulation, and the capacity to activate NK cells. Since the function of NK cells is impaired in tumor-bearing state, the administration of normal NK cells could significantly augment the efficiency of tumor therapy based on neutrophil priming. These findings highlight the reversibility of neutrophil function in tumor-bearing state, and suggest that neutrophil priming by IFN-γ/TNF-α might be a potential approach to eliminate residual tumor cells in comprehensive strategy for tumor therapy.

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Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF-α and PGE2

Cited by 26 publications

References 43 publications

Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

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

Neutrophils with protumor potential could efficiently suppress tumor growth after cytokine priming and in presence of normal NK cells

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