Effects of prostaglandin F2α (PGF2α) on cell-death pathways in the bovine corpus luteum (CL)

Abstract Background Prostaglandin F2α (PGF2α) may differentially affect viability of luteal cells by inducing either proliferation or cell death (via apoptosis or necroptosis). The diverse effects of PGF2α may depend on its local vs. systemic actions. In our study, we determined changes in expression of genes related to: (i) apoptosis: caspase (CASP) 3, CASP8, BCL2 associated X (BAX), B-cell lymphoma 2 (BCL2) and (ii) necroptosis: receptor-interacting protein kinase (RIPK) 1, RIPK3, cylindromatosis (CYLD), and mixed lineage kinase domain-like (MLKL) in the early and mid-stage corpus luteum (CL) that accompany local (intra-CL) vs. systemic (i.m.) analogue of PGF2α (aPGF2α) actions. Cows at day 4 (n = 24) or day 10 (n = 24) of the estrous cycle were treated by injections as follows: (1) systemic saline, (2) systemic aPGF2α (25 mg; Dinoprost), (3) local saline, (4) local aPGF2α (2.5 mg; Dinoprost). After 4 h, CLs were collected by ovariectomy. Expression levels of mRNA and protein were investigated by RT-q PCR, Western blotting and immunohistochemistry, respectively. Results We found that local and systemic administration of aPGF2α in the early-stage CL resulted in decreased expression of CASP3 (P < 0.01), but CASP8 mRNA expression was up-regulated (P < 0.05). However, the expression of CASP3 was up-regulated after local aPGF2α treatment in the middle-stage CL, whereas systemic aPGF2α administration increased both CASP3 and CASP8 expression (P < 0.01). Moreover, we observed that both local and systemic aPGF2α injections increased RIPK1, RIPK3 and MLKL expression in the middle-stage CL (P < 0.05) while CYLD expression was markedly higher after i.m. aPGF2α injections (P < 0.001). Moreover, we investigated the localization of necroptotic factors (RIPK1, RIPK3, CYLD and MLKL) in bovine CL tissue after local and systemic aPGF2α injections in the bovine CL. Conclusion Our results demonstrated for the first time that genes related to cell death pathways exhibit stage-specific responses to PGF2α administration depending on its local or systemic actions. Locally-acting PGF2α plays a luteoprotective role by inhibiting apoptosis and necroptosis in the early CL. Necroptosis is a potent mechanism responsible for structural CL regression during PGF2α-induced luteolysis in cattle.

Download Full-text

Mouse cytomegalovirus M36 and M45 death suppressors cooperate to prevent inflammation resulting from antiviral programmed cell death pathways

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1616829114 ◽

2017 ◽

Vol 114 (13) ◽

pp. E2786-E2795 ◽

Cited By ~ 22

Author(s):

Lisa P. Daley-Bauer ◽

Linda Roback ◽

Lynsey N. Crosby ◽

A. Louise McCormick ◽

Yanjun Feng ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Double Mutant ◽

Kinase Domain ◽

Murine Cytomegalovirus ◽

Caspase 8 ◽

Interacting Protein ◽

Antiviral Responses ◽

Cell Death Pathways ◽

Infected Cells

The complex interplay between caspase-8 and receptor-interacting protein (RIP) kinase RIP 3 (RIPK3) driving extrinsic apoptosis and necroptosis is not fully understood. Murine cytomegalovirus triggers both apoptosis and necroptosis in infected cells; however, encoded inhibitors of caspase-8 activity (M36) and RIP3 signaling (M45) suppress these antiviral responses. Here, we report that this virus activates caspase-8 in macrophages to trigger apoptosis that gives rise to secondary necroptosis. Infection with double-mutant ΔM36/M45mutRHIM virus reveals a signaling pattern in which caspase-8 activates caspase-3 to drive apoptosis with subsequent RIP3-dependent activation of mixed lineage kinase domain-like (MLKL) leading to necroptosis. This combined cell death signaling is highly inflammatory, greater than either apoptosis induced by ΔM36 or necroptosis induced by M45mutRHIM virus. IL-6 production by macrophages is dramatically increased during double-mutant virus infection and correlates with faster antiviral responses in the host. Collaboratively, M36 and M45 target caspase-8 and RIP3 pathways together to suppress this proinflammatory cell death. This study reveals the effect of antiviral programmed cell death pathways on inflammation, shows that caspase-8 activation may go hand-in-hand with necroptosis in macrophages, and revises current understanding of independent and collaborative functions of M36 and M45 in blocking apoptotic and necroptotic cell death responses.

Download Full-text

Regulation of Necroptosis by Phospholipids and Sphingolipids

Cells ◽

10.3390/cells9030627 ◽

2020 ◽

Vol 9 (3) ◽

pp. 627 ◽

Cited By ~ 2

Author(s):

Xuewei Zhang ◽

Masaya Matsuda ◽

Nobuo Yaegashi ◽

Takeshi Nabe ◽

Kazuyuki Kitatani

Keyword(s):

Cell Death ◽

Protein Kinases ◽

Kinase Domain ◽

Interacting Protein ◽

Mixed Lineage Kinase ◽

Cell Death Pathways ◽

Regulated Cell Death

Several non-apoptotic regulated cell death pathways have been recently reported. Necroptosis, a form of necrotic-regulated cell death, is characterized by the involvement of receptor-interacting protein kinases and/or the pore-forming mixed lineage kinase domain-like protein. Recent evidence suggests a key role for lipidic molecules in the regulation of necroptosis. The purpose of this mini-review is to outline the regulation of necroptosis by sphingolipids and phospholipids.

Download Full-text

Expression of prostaglandin G/H synthase (PGHS) and heat shock protein-70 (HSP-70) in the corpus luteum (CL) of prostaglandin F2α-treated immature superovulated rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y04-032 ◽

2004 ◽

Vol 82 (6) ◽

pp. 363-371 ◽

Cited By ~ 9

Author(s):

R M Narayansingh ◽

M Senchyna ◽

M M Vijayan ◽

J C Carlson

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Protein Expression ◽

Corpus Luteum ◽

Heat Shock Protein 70 ◽

Prostaglandin F2α ◽

Sampling Period ◽

Immunoblot Analysis ◽

Hsp 70 ◽

Prostaglandin F

In this study we examined the mechanism of corpus luteum (CL) regression by measuring changes in expression of prostaglandin G/H synthase-1 (PGHS-1) and -2 (PGHS-2) in day 4 CL and inducible heat shock protein 70 (HSP-70) in day 4 and day 9 CL of immature superovulated rats. The rats were superovulated and treated with 500 µg of prostaglandin F2α (PGF2α) on day 4 or day 9 after CL formation. Ovaries and serial blood samples were removed during the 24-hour period following treatment. Plasma progesterone was determined by radioimmunoassay while mRNA abundance and protein expression were assessed by semiquantitative RT-PCR and immunoblot analysis, respectively. One hour after PGF2α, both day 4 and day 9 rats exhibited a significant decrease in progesterone secretion; however, there was a greater decrease in day 9 rats. In ovarian samples removed on day 4, there was a significant increase in mRNA for PGHS-2 at 1 hour after PGF2α. PGHS-1 mRNA content remained unchanged. Immunoblot analyses showed an increase in PGHS-2 protein expression only at 8 h. There were no changes in PGHS-1 protein expression. In day 9 rats, ovarian HSP-70 protein levels increased by 50% after PGF2α injection; however, on day 4 there was no change in expression of this protein over the sampling period. These results suggest that expression of PGHS-2 may be involved in inhibiting progesterone production and that expression of HSP-70 may be required for complete CL regression in the rat.Key words: rat, prostaglandin F2α, corpus luteum, prostaglandin G/H synthase, heat shock protein-70.

Download Full-text

MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707531114 ◽

2017 ◽

Vol 114 (36) ◽

pp. E7450-E7459 ◽

Cited By ~ 52

Author(s):

Shuzhen Liu ◽

Hua Liu ◽

Andrea Johnston ◽

Sarah Hanna-Addams ◽

Eduardo Reynoso ◽

...

Keyword(s):

Cell Death ◽

Disulfide Bond ◽

Kinase Domain ◽

Proteinase K ◽

Interacting Protein ◽

Tnf Α ◽

Mouse Cells ◽

Red Dye ◽

Necessary And Sufficient ◽

Human And Mouse

Mixed-lineage kinase domain-like protein (MLKL) is essential for TNF-α–induced necroptosis. How MLKL promotes cell death is still under debate. Here we report that MLKL forms SDS-resistant, disulfide bond-dependent polymers during necroptosis in both human and mouse cells. MLKL polymers are independent of receptor-interacting protein kinase 1 and 3 (RIPK1/RIPK3) fibers. Large MLKL polymers are more than 2 million Da and are resistant to proteinase K digestion. MLKL polymers are fibers 5 nm in diameter under electron microscopy. Furthermore, the recombinant N-terminal domain of MLKL forms amyloid-like fibers and binds Congo red dye. MLKL mutants that cannot form polymers also fail to induce necroptosis efficiently. Finally, the compound necrosulfonamide conjugates cysteine 86 of human MLKL and blocks MLKL polymer formation and subsequent cell death. These results demonstrate that disulfide bond-dependent, amyloid-like MLKL polymers are necessary and sufficient to induce necroptosis.

Download Full-text

The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils

Science Signaling ◽

10.1126/scisignal.aao1716 ◽

2018 ◽

Vol 11 (546) ◽

pp. eaao1716 ◽

Cited By ~ 13

Author(s):

Akshay A. D’Cruz ◽

Mary Speir ◽

Meghan Bliss-Moreau ◽

Sylvia Dietrich ◽

Shu Wang ◽

...

Keyword(s):

Cell Death ◽

Kinase Domain ◽

Neutrophil Extracellular Trap ◽

Human Neutrophils ◽

Caspase 8 ◽

Interacting Protein ◽

Dependent Activity ◽

Mrsa Infection ◽

Death Effector ◽

Net Release

Neutrophil extracellular trap (NET) formation can generate short-term, functional anucleate cytoplasts and trigger loss of cell viability. We demonstrated that the necroptotic cell death effector mixed lineage kinase domain–like (MLKL) translocated from the cytoplasm to the plasma membrane and stimulated downstream NADPH oxidase–independent ROS production, loss of cytoplasmic granules, breakdown of the nuclear membrane, chromatin decondensation, histone hypercitrullination, and extrusion of bacteriostatic NETs. This process was coordinated by receptor-interacting protein kinase-1 (RIPK1), which activated the caspase-8–dependent apoptotic or RIPK3/MLKL-dependent necroptotic death of mouse and human neutrophils. Genetic deficiency of RIPK3 and MLKL prevented NET formation but did not prevent cell death, which was because of residual caspase-8–dependent activity. Peptidylarginine deiminase 4 (PAD4) was activated downstream of RIPK1/RIPK3/MLKL and was required for maximal histone hypercitrullination and NET extrusion. This work defines a distinct signaling network that activates PAD4-dependent NET release for the control of methicillin-resistant Staphylococcus aureus (MRSA) infection.

Download Full-text

Genetic Regulation of RIPK1 and Necroptosis

Annual Review of Genetics ◽

10.1146/annurev-genet-071719-022748 ◽

2021 ◽

Vol 55 (1) ◽

pp. 235-263

Author(s):

Daichao Xu ◽

Chengyu Zou ◽

Junying Yuan

Keyword(s):

Cell Death ◽

Protein Kinase ◽

Genetic Regulation ◽

Caspase 8 ◽

Inflammatory Signaling ◽

Interacting Protein ◽

Multiple Factors ◽

Cell Death Pathways ◽

Upstream Regulator ◽

Multiple Cell

The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.

Download Full-text

Necroptosis in Cholangiocarcinoma

Cells ◽

10.3390/cells9040982 ◽

2020 ◽

Vol 9 (4) ◽

pp. 982

Author(s):

Samantha Sarcognato ◽

Iris E. M. de Jong ◽

Luca Fabris ◽

Massimiliano Cadamuro ◽

Maria Guido

Keyword(s):

Cell Death ◽

Current Knowledge ◽

Kinase Domain ◽

Alternative Mode ◽

Interacting Protein ◽

Regulated Cell Death ◽

Anti Cancer ◽

Regulatory Complex ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Necroptosis is a type of regulated cell death that is increasingly being recognized as a relevant pathway in different pathological conditions. Necroptosis can occur in response to multiple stimuli, is triggered by the activation of death receptors, and is regulated by receptor-interacting protein kinases 1 and 3 and mixed-lineage kinase domain-like, which form a regulatory complex called the necrosome. Accumulating evidence suggests that necroptosis plays a complex role in cancer, which is likely context-dependent and can vary among different types of neoplasms. Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis and, as a pro-inflammatory death type, it may inhibit tumor progression by releasing damage-associated molecular patterns to elicit robust cross-priming of anti-tumor CD8+ T cells. The development of therapeutic strategies triggering necroptosis shows great potential for anti-cancer therapy. In this review, we summarize the current knowledge on necroptosis and its role in liver biliary neoplasms, underlying the potential of targeting necroptosis components for cancer treatment.

Download Full-text

The novel cyclophilin-D-interacting protein FASTKD1 protects cells against oxidative stress-induced cell death

AJP Cell Physiology ◽

10.1152/ajpcell.00471.2018 ◽

2019 ◽

Vol 317 (3) ◽

pp. C584-C599

Author(s):

Kurt D. Marshall ◽

Paula J. Klutho ◽

Lihui Song ◽

Maike Krenz ◽

Christopher P. Baines

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Kinase Domain ◽

Protective Role ◽

Mitochondrial Morphology ◽

Cyclophilin D ◽

Interacting Protein ◽

Mitochondrial Homeostasis

Opening of the mitochondrial permeability transition (MPT) pore leads to necrotic cell death. Excluding cyclophilin D (CypD), the makeup of the MPT pore remains conjecture. The purpose of these experiments was to identify novel MPT modulators by analyzing proteins that associate with CypD. We identified Fas-activated serine/threonine phosphoprotein kinase domain-containing protein 1 (FASTKD1) as a novel CypD interactor. Overexpression of FASTKD1 protected mouse embryonic fibroblasts (MEFs) against oxidative stress-induced reactive oxygen species (ROS) production and cell death, whereas depletion of FASTKD1 sensitized them. However, manipulation of FASTKD1 levels had no effect on MPT responsiveness, Ca2+-induced cell death, or antioxidant capacity. Moreover, elevated FASTKD1 levels still protected against oxidative stress in CypD-deficient MEFs. FASTKD1 overexpression decreased Complex-I-dependent respiration and ΔΨm in MEFs, effects that were abrogated in CypD-null cells. Additionally, overexpression of FASTKD1 in MEFs induced mitochondrial fragmentation independent of CypD, activation of Drp1, and inhibition of autophagy/mitophagy, whereas knockdown of FASTKD1 had the opposite effect. Manipulation of FASTKD1 expression also modified oxidative stress-induced caspase-3 cleavage yet did not alter apoptotic death. Finally, the effects of FASTKD1 overexpression on oxidative stress-induced cell death and mitochondrial morphology were recapitulated in cultured cardiac myocytes. Together, these data indicate that FASTKD1 supports mitochondrial homeostasis and plays a critical protective role against oxidant-induced death.

Download Full-text

CONCENTRATION OF PROSTAGLANDIN F2α AND STEROIDS IN THE HUMAN CORPUS LUTEUM

Journal of Endocrinology ◽

10.1677/joe.0.0730115 ◽

1977 ◽

Vol 73 (1) ◽

pp. 115-122 ◽

Cited By ~ 38

Author(s):

I. A. SWANSTON ◽

K. P. McNATTY ◽

D. T. BAIRD

Keyword(s):

Menstrual Cycle ◽

Corpus Luteum ◽

Luteal Phase ◽

Prostaglandin F2α ◽

Corpora Lutea ◽

Progesterone Concentration ◽

Late Luteal Phase ◽

Prostaglandin F ◽

Human Corpus Luteum

SUMMARY The concentration of prostaglandin F2α (PGF2α), progesterone, pregnenolone, oestradiol-17β, oestrone, androstenedione and testosterone was measured in corpora lutea obtained from 40 women at various stages of the menstrual cycle. The concentration of PGF2α was significantly higher in corpora lutea immediately after ovulation (26·7 ± 3·9 (s.e.m.) ng/g, P < 0·005) and in corpora albicantia (16·3 ± 3·3 ng/g, P < 0·005) than at any other time during the luteal phase. There was no correlation between the concentration of PGF2α and that of any steroid. The progesterone concentration was highest in corpora lutea just after ovulation (24·9 ± 6·7 μg/g) and in early luteal groups (25·7 ± 6·8 μg/g) but declined significantly (P < 0·05) to its lowest level in corpora albicantia (1·82 ± 0·66 μg/g). The concentration of oestradiol-17β in the corpus luteum and luteal weight were significantly greater during the mid-luteal phase than at any other stage (concentration 282 ± 43 ng/g, P < 0·05; weight 1·86 ± 0·18 g, P < 0·005). The results indicate that regression of the human corpus luteum is not caused by a rise in the ovarian concentration of PGF2α in the late luteal phase of the cycle.

Download Full-text

Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

10.20944/preprints202009.0084.v1 ◽

2020 ◽

Author(s):

Anna Negroni ◽

Eleonora Colantoni ◽

Salvatore Cucchiara ◽

Laura Stronati

Keyword(s):

Cell Death ◽

Intestinal Epithelium ◽

Inflammatory Cell ◽

Intestinal Inflammation ◽

Inflammatory Diseases ◽

Kinase Domain ◽

Interacting Protein ◽

New Concepts ◽

Independent Form ◽

Cellular Turnover

Necroptosis is a caspases-independent form of programmed cell death exhibiting intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development, tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis has been associated to chronic inflammatory diseases and cancer. Drugs that inhibit necroptosis could, therefore, be used therapeutically for the treatment of these diseases, and researches to develop such inhibitors are already underway. In this Review, we outline pathways for necroptosis and its role in chronic inflammation and cancer. We also discuss current and developing therapies that target necroptosis machinery.

Download Full-text