Interferon α Induces Nucleus-independent Apoptosis by Activating Extracellular Signal-regulated Kinase 1/2 and c-Jun NH<sub>2</sub>-Terminal Kinase Downstream of Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin

Panaretakis, Theocharis; Hjortsberg, Linn; Tamm, Katja Pokrovskaja; Björklund, Ann Charlotte; Joseph, Bertrand; Grandér, Dan

doi:10.1091/mbc.e07-04-0358

Cited by 45 publications

(36 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4B). A role for BAK in DC apoptosis triggered by microbial stimuli as well as by IFN-b has not been described before, but a central role for BAK in IFN-a-mediated and Semliki Forest virus-mediated apoptosis has been reported in other cellular systems (45,46). Extending these notions, BAK may also regulate apoptosis in immature DCs, as suggested by our Western blot analysis (Fig.…”

Section: Discussionsupporting

confidence: 78%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 78%

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

View full text Add to dashboard Cite

show abstract

“…Addition of the ERK MAP kinase inhibitor U0126 prevented the death of RAW cells in the presence of ATCV-1. Other reports show the involvement of ERK MAP kinase in activation of apoptosis of cells in response to DNA-damaging agents (49) and type I IFNs (23). The mechanism by which ATCV-1 induces activation of ERK MAP kinases or apoptotic programmed cell death is unknown.…”

Section: Discussionmentioning

confidence: 96%

Response of Mammalian Macrophages to Challenge with the Chlorovirus Acanthocystisturfacea Chlorella Virus 1

Petro

Agarkova

Zhou

et al. 2015

J Virol

View full text Add to dashboard Cite

It was recently reported that 44% of the oropharyngeal samples from the healthy humans in a study cohort had DNA sequences similar to that of the chlorovirus ATCV-1 (Acanthocystis turfacea chlorella virus 1, family Phycodnaviridae) and that these study subjects had decreases in visual processing and visual motor speed compared with individuals in whom no virus was detected. Moreover, mice inoculated orally with ATCV-1 developed immune responses to ATCV-1 proteins and had decreases in certain cognitive domains. Because heightened interleukin-6 (IL-6), nitric oxide (NO), and ERK mitogen-activated protein (MAP) kinase activation from macrophages are linked to cognitive impairments, we evaluated cellular responses and viral PFU counts in murine RAW264.7 cells and primary macrophages after exposure to ATCV-1 in vitro for up to 72 h after a virus challenge. Approximately 8% of the ATCV-1 inoculum was associated with macrophages after 1 h, and the percentage increased 2-to 3-fold over 72 h. Immunoblot assays with rabbit anti-ATCV-1 antibody detected a 55-kDa protein consistent with the viral capsid protein from 1 to 72 h and increasing de novo synthesis of a previously unidentified 17-kDa protein beginning at 24 h. Emergence of the 17-kDa protein did not occur and persistence of the 55-kDa protein declined over time when cells were exposed to heat-inactivated ATCV-1. Moreover, starting at 24 h, RAW264.7 cells exhibited cytopathic effects, annexin V staining, and cleaved caspase 3. Activation of ERK MAP kinases occurred in these cells by 30 min postchallenge, which preceded the expression of IL-6 and NO. Therefore, ATCV-1 persistence in and induction of inflammatory factors by these macrophages may contribute to declines in the cognitive abilities of mice and humans. IMPORTANCEVirus infections that persist in and stimulate inflammatory factors in macrophages contribute to pathologies in humans. A previous study showed that DNA sequences homologous to the chlorovirus ATCV-1 were found in a significant fraction of oropharyngeal samples from a healthy human cohort. We show here that ATCV-1, whose only known host is a eukaryotic green alga (Chlorella heliozoae) that is an endosymbiont of the heliozoon Acanthocystis turfacea, can unexpectedly persist within murine macrophages and trigger inflammatory responses including factors that contribute to immunopathologies. The inflammatory factors that are produced in response to ATCV-1 include IL-6 and NO, whose induction is preceded by the activation of ERK MAP kinases. Other responses of ATCV-1-challenged macrophages include an apoptotic cytopathic effect, an innate antiviral response, and a metabolic shift toward aerobic glycolysis. Therefore, mammalian encounters with chloroviruses may contribute to chronic inflammatory responses from macrophages. C hloroviruses (family Phycodnaviridae) were discovered over 35 years ago and are distinctive because they are large icosahedral double-stranded DNA (dsDNA) viruses that infect certain unicellular eukaryotic green algae, which...

show abstract

“…The most obvious mechanism would be through the activation of TNF receptors by Fas (51), TRAIL (38,52), or TNF. Conversely, Panaretakis et al (17) suggested previously that interferon induces apoptosis through PI3K, which activates the downstream extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase C␦ (PKC␦), and JNK genes, leading to intrinsic apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…In melanomas, IFN-␤ was more potent in inducing a proapoptotic effect than IFN-␣2, yet the same melanoma cell lines were resistant to recombinant TRAIL protein, with no significant role identified for apoptosis inhibitors such as cFLIP, survivin, or cIAPs. An alternative signaling pathway through phosphatidylinositol 3-kinase (PI3K) and mTOR was previously suggested to drive interferon-induced apoptosis, with ISG activation being insufficient for apoptosis induction (16)(17)(18)(19). Although the hypotheses are not contradictory, the underlining molecular basis of the antiproliferative activity is still debatable.…”

mentioning

confidence: 99%

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Apelbaum

Yarden

Warszawski

et al. 2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

Interferons induce a pleiotropy of responses through binding the same cell surface receptor. Here we investigated the molecular mechanism driving interferon-induced apoptosis. Using a nonbiased small interfering RNA (siRNA) screen, we show that silencing genes whose products are directly engaged in the initiation of interferon signaling completely abrogate the interferon antiproliferative response. Apoptosis-related genes such as the caspase-8, cFLIP, and DR5 genes specifically interfere with interferon-induced apoptosis, which we found to be independent of the activity of death ligands. The one gene for which silencing resulted in the strongest proapoptotic effect upon interferon signaling is the cFLIP gene, where silencing shortened the time of initiation of apoptosis from days to hours and increased dramatically the population of apoptotic cells. Thus, cFLIP serves as a regulator for interferon-induced apoptosis. A shift over time in the balance between cFLIP and caspase-8 results in downstream caspase activation and apoptosis. While gamma interferon (IFN-␥) also causes caspase-8 upregulation, we suggest that it follows a different path to apoptosis.

show abstract

Interferon α Induces Nucleus-independent Apoptosis by Activating Extracellular Signal-regulated Kinase 1/2 and c-Jun NH₂-Terminal Kinase Downstream of Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin

Abstract: Interferon (IFN)␣ induces apoptosis via Bak and

Cited by 45 publications

References 40 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

Response of Mammalian Macrophages to Challenge with the Chlorovirus Acanthocystisturfacea Chlorella Virus 1

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Contact Info

Product

Resources

About

Interferon α Induces Nucleus-independent Apoptosis by Activating Extracellular Signal-regulated Kinase 1/2 and c-Jun NH2-Terminal Kinase Downstream of Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin

Abstract: Interferon (IFN)␣ induces apoptosis via Bak and

Cited by 45 publications

References 40 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

Response of Mammalian Macrophages to Challenge with the Chlorovirus Acanthocystisturfacea Chlorella Virus 1

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Contact Info

Product

Resources

About

Interferon α Induces Nucleus-independent Apoptosis by Activating Extracellular Signal-regulated Kinase 1/2 and c-Jun NH₂-Terminal Kinase Downstream of Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin