Interleukin-1β (IL-1β) is a potent inflammatory cytokine that is usually cleaved and activated by inflammasome-associated caspase-1. To determine whether IL-1β activation is regulated by inhibitor of ...apoptosis (IAP) proteins, we treated macrophages with an IAP-antagonist “Smac mimetic” compound or genetically deleted the genes that encode the three IAP family members cIAP1, cIAP2, and XIAP. After Toll-like receptor priming, IAP inhibition triggered cleavage of IL-1β that was mediated not only by the NLRP3-caspase-1 inflammasome, but also by caspase-8 in a caspase-1-independent manner. In the absence of IAPs, rapid and full generation of active IL-1β by the NLRP3-caspase-1 inflammasome, or by caspase-8, required the kinase RIP3 and reactive oxygen species production. These results demonstrate that activation of the cell death-inducing ripoptosome platform and RIP3 can generate bioactive IL-1β and implicate them as additional targets for the treatment of pathological IL-1-driven inflammatory responses.
Display omitted
► IAP inhibition induces NLRP3 inflammasome-dependent and -independent IL-1 activation ► Genetic deletion of the three IAPs (cIAP1, cIAP2, XIAP) activates IL-1 ► Inflammasome-independent IL-1 maturation is mediated by caspase-8 cleavage ► RIP3 signaling, and not cell death, activates IL-1
RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive ...inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3-caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1β inflammatory responses independent of MLKL and necroptotic cell death.
The precise value of the mean neutron lifetime, τ
, plays an important role in nuclear and particle physics and cosmology. It is used to predict the ratio of protons to helium atoms in the primordial ...universe and to search for physics beyond the Standard Model of particle physics. We eliminated loss mechanisms present in previous trap experiments by levitating polarized ultracold neutrons above the surface of an asymmetric storage trap using a repulsive magnetic field gradient so that the stored neutrons do not interact with material trap walls. As a result of this approach and the use of an in situ neutron detector, the lifetime reported here 877.7 ± 0.7 (stat) +0.4/-0.2 (sys) seconds does not require corrections larger than the quoted uncertainties.
The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that ...antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.
Display omitted
•Tumors expressing Fn14 cause cachexia in mice•Fn14 antibodies extend lifespan by inhibiting tumor-induced cachexia•Fn14- and TWEAK-deficient mice succumb to cancer cachexia•Tumor Fn14 signaling, rather than host, is responsible for inducing cachexia
Antibodies against the TWEAK receptor Fn14 prevent tumor-induced cachexia and extend lifespan by inhibiting weight loss and inflammation, although having only moderate effects on tumor growth.
The International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) have initiated a series of cancer-focused seminars Scelo G, Hofmann JN, Banks RE et al. International ...cancer seminars: a focus on kidney cancer. Ann Oncol 2016; 27(8): 1382–1385. In this, the second seminar, IARC and NCI convened a workshop in order to examine the state of the current science on esophageal squamous cell carcinoma etiology, genetics, early detection, treatment, and palliation, was reviewed to identify the most critical open research questions. The results of these discussions were summarized by formulating a series of ‘difficult questions’, which should inform and prioritize future research efforts.
Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render ...cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant.
•Genetic loss or chemical inhibition of p38 or MK2 increases SM-induced TNF•p38 and MK2 inhibit SM-induced phosphorylation of JNK and ERK•The combination of SM and p38 inhibitor is well tolerated in vivo•p38 and MK2 inhibitors potentiate SM killing of AML in vivo
Lalaoui et al. show that inhibition of p38 or its downstream kinase MK2, in contrast to reducing Toll-like receptor-mediated tumor necrosis factor (TNF) production, increases TNF production upon smac-mimetic (SM) treatment and enhances the anti-tumor efficacy of SM.
Loss of inhibitor of apoptosis proteins (IAPs), particularly cIAP1, can promote production of tumor necrosis factor (TNF) and sensitize cancer cell lines to TNF-induced necroptosis by promoting ...formation of a death-inducing signaling complex containing receptor-interacting serine/threonine-protein kinase (RIPK) 1 and 3. To define the role of IAPs in myelopoiesis, we generated a mouse with cIAP1, cIAP2, and XIAP deleted in the myeloid lineage. Loss of cIAPs and XIAP in the myeloid lineage caused overproduction of many proinflammatory cytokines, resulting in granulocytosis and severe sterile inflammation. In vitro differentiation of macrophages from bone marrow in the absence of cIAPs and XIAP led to detectable levels of TNF and resulted in reduced numbers of mature macrophages. The cytokine production and consequent cell death caused by IAP depletion was attenuated by loss or inhibition of TNF or TNF receptor 1. The loss of RIPK1 or RIPK3, but not the RIPK3 substrate mixed lineage kinase domain-like protein, attenuated TNF secretion and thereby prevented apoptotic cell death and not necrosis. Our results demonstrate that cIAPs and XIAP together restrain RIPK1- and RIPK3-dependent cytokine production in myeloid cells to critically regulate myeloid homeostasis.
•cIAPs and XIAP negatively regulate cytokine production, including TNF to disrupt myeloid lineage differentiation.•IAPs prevent RIPK1 and RIPK3 activity to limit cytokine production prior to cell death.
To estimate the burden of osteoarthritis (OA) among noninstitutionalized adults (≥18 years of age) in the US.
Weighted nationally representative data from the 2015 Medical Expenditure Panel Survey ...were used to estimate OA prevalence in noninstitutionalized adults and compare adults with OA to those without OA for clinical (pain interference with activities PIA, functional limitations), humanistic (health-related quality-of-life HRQoL) and economic outcomes (healthcare costs, wage loss). Productivity/wage loss was estimated among employed working-age adults (18–64 years). Multivariable regression analyses examined the associations between OA and outcomes.
In 2015, 10.5% (25.6 million) of noninstitutionalized US adults reported having any OA. Regression analyses indicated that adults with OA were significantly more likely than those without OA to report moderate (adjusted odds ratios AOR 1.99; 95% confidence interval CI 1.65–2.40 or severe PIA (AOR 2.59; 95% CI 2.21–3.04), any functional limitation (AOR 2.51; 95% CI 2.21–2.85), and poorer HRQoL on the SF-12 version 2 Physical Component Summary score (adjusted beta standard error −3.88 0.357; P < 0.001). Adjusted incremental annual total healthcare costs and lost wages among adults with OA relative to those without OA were $1778 and $189 per person, respectively, resulting in estimated national excess costs of $45 billion and $1.7 billion, respectively.
OA affects approximately 10% of noninstitutionalized adults in the US, resulting in substantial clinical, humanistic, and economic burdens.
As agricultural land and freshwater inextricably interrelate and interact with each other, the conventional water and land policy in “silos” should give way to nexus thinking when formulating the ...land and water management strategies. This study constructs a systems multi-regional input-output (MRIO) model to expound global land-water nexus by simultaneously tracking agricultural land and freshwater use flows along the global supply chains. Furthermore, land productivity and irrigation water requirements of 160 crops in different regions are investigated to reflect the land-water linkage. Results show that developed economies (e.g., USA and Japan) and major large developing economies (e.g., mainland China and India) are the overriding drivers of agricultural land and freshwater use globally. In general, significant net transfers of these two resources are identified from resource-rich and less-developed economies to resource-poor and more-developed economies. For some crops, blue water productivity is inversely related to land productivity, indicating that irrigation water consumption is sometimes at odds with land use. The results could stimulus international cooperation for sustainable land and freshwater management targeting on original suppliers and final consumers along the global supply chains. Moreover, crop-specific land-water linkage could provide insights for trade-off decisions on minimizing the environmental impacts on local land and water resources.
Display omitted
•Agricultural land and freshwater use within global supply chains are tracked simultaneously.•Land productivity and irrigation water requirements of 160 crops in different regions are investigated.•Approximately one-third of land use and water withdrawal is attributed to interregional trade.•Trade-off decisions should be made for both local agricultural production and global supply chain management.
Arsenic in groundwater caused the black‐foot disease (BFD) in many countries in the 1950–1960s. It is of great importance to develop a feasible method for removal of arsenic from contaminated ...groundwater in BFD endemic areas. Photocatalytic oxidation of As(III) to less toxic As(V) is, therefore, of significance for preventing any arsenic‐related disease that may occur. By in situ synchrotron X‐ray absorption spectroscopy, the formation of As(V) is related to the expense of As(III) disappearance during photocatalysis by TiO2 nanotubes (TNTs). Under UV/Vis light irradiation, the apparent first‐order rate constant for the photocatalytic oxidation of As(III) to As(V) is 0.0148 min−1. It seems that As(III) can be oxidized with photo‐excited holes while the not‐recombined electrons may be scavenged with O2 in the channels of the well defined TNTs (an opening of 7 nm in diameter). In the absence of O2, on the contrary, As(III) can be reduced to As(0), to some extent. Cu(II) (CuO), as an electron acceptor, was impregnated on the TNTs surfaces in order to gain a better understanding of electron transfer during photocatalysis. It appears that As(III) can be oxidized to As(V) while Cu(II) is reduced to Cu(I) and Cu(0). The molecular‐scale data are very useful in revealing the oxidation states and interconversions of arsenic during the photocatalytic reactions. This work has implications in that the toxicity of arsenic in contaminated groundwater or wastewater can be effectively decreased via solar‐driven photocatalysis, which may facilitate further treatments by coagulation.
The photocatalytic oxidation of As(III) to less toxic As(V) by TiO2 nanotubes studied using in situ synchrotron X‐ray absorption spectroscopy is presented.
PDF
