RESUMEN
The absence of tumor-infiltrating lymphocytes negatively impacts the response to chemotherapy and prognosis in all subtypes of breast cancer. Therapies that stimulate a proinflammatory environment may help improve the response to standard treatments and also to immunotherapies such as checkpoint inhibitors. Newcastle disease virus (NDV) shows oncolytic activity, as well as immune modulating potential, in the treatment of breast cancer in vitro and in vivo; however, its potential to enhance tumor-infiltrating immune cells in breast cancer has yet to be evaluated. Since spontaneous canine mammary tumors represent a translational model of human breast cancer, we conducted this proof-of-concept study, which could provide a rationale for further investigating NDV-MLS as immunotherapy for mammary cancer. Six female companion dogs with spontaneous mammary cancer received a single intravenous and intratumoral injection of oncolytic NDV-MLS. Immune cell infiltrates were evaluated by histology and immunohistochemistry in the stromal, intratumoral, and peritumoral compartments on day 6 after viral administration. Increasing numbers of immune cells were documented post-viral treatment, mainly in the peritumoral compartment, where plasma cells and CD3+ and CD3-/CD79- lymphocytes predominated. Viral administration was well tolerated, with no significant adverse events. These findings support additional research on the use of NDV-MLS immunotherapy for mammary cancer.
Asunto(s)
Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Animales , Femenino , Perros , Virus de la Enfermedad de Newcastle/fisiología , Mascotas , Virus Oncolíticos/fisiología , Inmunoterapia , Línea Celular Tumoral , Neoplasias/terapiaRESUMEN
Inflammasomes are multiprotein complexes that play a role in the processing of proinflammatory cytokines such as interleukin 1 beta (IL-1ß). The secretion of IL-1ß in bovine macrophages infected with the bovine viral diarrhea virus (BVDV) cytopathic strain NADL (NADLcp-BVDV) is caspase 1-dependent. In the present study, we found that in macrophages infected with NADL, the NLRP3 inflammasome participated in the maturation of IL-1ß as the level decreased from 4629.3 pg/mL to 897.0 pg/mL after treatment with cytokine release inhibitory drug 3 (CRID3). Furthermore, NLRP3 activation has implications regarding viral replication, as there was a decrease in the viral titer until 1 log of a supernatant of macrophages that were inhibited with CRID3 remained. In the case of the non-cytopathic BVDV strain NY-1 (NY-1 ncpBVDV), IL-1ß secretion is not affected by NLRP3, but could be related to the IFI16 inflammasome; we found a colocalization of IFI16 with ASC using confocal microscopy in infected macrophages with the NY-1 ncp-BVDV biotype. To relate IFI16 activation to IL-1ß release, we used ODN TTAGGG (A151), a competitive inhibitor of IFI16; the results show a decrease in its level from 248 pg/mL to 128.3 pg/mL. Additionally, we evaluated the caspase 1 activation downstream of IFI16 and found a decrease in the IL-1ß from 252.9 pg/mL to 63.5 pg/mL when caspase 1 was inhibited with Y-VAD. Our results provide an improved understanding of the mechanisms involved in the viral replication, inflammation and pathogenesis of bovine viral diarrhea.
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Virus de la Diarrea Viral Bovina Tipo 1 , Virus de la Diarrea Viral Bovina , Caspasa 1 , Citocinas , Diarrea , Inflamasomas , Interleucina-1beta , Macrófagos , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas Nucleares , Fosfoproteínas , Replicación Viral , Animales , BovinosRESUMEN
The aim of this work was to determine endometrial mRNA expression and uterine protein localization of vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2 during the estrous cycle and peri-implantation period in sows. Uterine tissues were collected from pregnant sows on days 12, 14, 16, and 18 after artificial insemination and from non-pregnant animals on days 2 and 12 of the estrous cycle (day 0 = day of estrus). Using immunohistochemistry, a positive signal for VEGF and its receptor VEGFR2 was found in uterine luminal epithelial cells, endometrial glands, stroma, blood vessels, and myometrium. A VEGFR1 signal was only found in endometrial and myometrial blood vessels and stroma. By day 18 of gestation, the mRNA expression levels of VEGF, VEGFR1, and VEGFR2 were higher than those observed on days 2 and 12 of the estrous cycle and on days 12, 14, and 16 of gestation. Then, a primary culture of sow endometrial epithelial cells was established to define the potential of the selective inhibition of VEGFR2 after treatment with inhibitor SU5416 and determine its effects on the expression pattern of the VEGF system. The endometrial epithelial cells treated with SU5416 showed a dose-dependent decrease in VEGFR1 and VEGFR2 mRNA expression. The present study provides additional evidence on the importance of the VEGF system during peri-implantation, as well as on the specific inhibitory activity of SU5416 in epithelial cells, which, as demonstrated, express the protein and mRNA of VEGF and its receptors VEGFR1 and VEGFR2.
Asunto(s)
Inhibidores de la Angiogénesis , Factor A de Crecimiento Endotelial Vascular , Animales , Porcinos , Femenino , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/metabolismo , Útero/metabolismo , Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , ARN Mensajero/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) are globally distributed retroviruses that infect domestic cats and cause various syndromes that can lead to death. The aim of this study was to detect and genotype feline retroviruses in Mexican domestic cats. We used PCR assays to identify proviral DNA and viral RNA in 50 domestic cats with different clinical signs and hematological alterations. Endogenous FeLV (enFeLV) was identified in the genomic DNA of all cats in the study, and we detected transcripts of the LTR region of enFeLV in 48 individuals. Exogenous FeLV (exFeLV) was found in 13 cats. Furthermore, we detected FIV proviral DNA in 10 cats. The enFeLV sequences were shown to be the most variable, while the exFeLV sequences were highly conserved and related to previously reported subgroup A sequences. Sequencing of the FIV gag gene revealed the presence of subtype B in the infected cats.
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Virus de la Inmunodeficiencia Felina , Leucemia Felina , Gatos , Animales , Retroviridae , Virus de la Leucemia Felina/genética , Provirus/genética , Virus de la Inmunodeficiencia Felina/genéticaRESUMEN
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current pandemic affecting almost all countries in the world. SARS-CoV-2 is the agent responsible for coronavirus disease 19 (COVID-19), which has claimed millions of lives around the world. In most patients, SARS-CoV-2 infection does not cause clinical signs. However, some infected people develop symptoms, which include loss of smell or taste, fever, dry cough, headache, severe pneumonia, as well as coagulation disorders. The aim of this work is to report genetic factors of SARS-CoV-2 and host-associated to severe COVID-19, placing special emphasis on the viral entry and molecules of the immune system involved with viral infection. Besides this, we analyze SARS-CoV-2 variants and their structural characteristics related to the binding to polymorphic angiotensin-converting enzyme type 2 (ACE2). Additionally, we also review other polymorphisms as well as some epigenetic factors involved in the immunopathogenesis of COVID-19. These factors and viral variability could explain the increment of infection rate and/or in the development of severe COVID-19.
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COVID-19/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo Genético/inmunología , SARS-CoV-2/genética , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Deriva y Cambio Antigénico , COVID-19/inmunología , COVID-19/virología , Variación Genética , Interacciones Huésped-Patógeno , Humanos , SARS-CoV-2/inmunologíaRESUMEN
Swine enteric viral infections are responsible for substantial economic losses in the pork industry worldwide. Porcine epidemic diarrhea (PEDV) is one of the main causative agents of diarrhea in lactating pigs, and reports of PEDV coinfection with other enteric viruses highlight the importance of viral interactions for disease presentation and outcomes. Using next-generation sequencing (NGS) and sequence analyses from samples taken from piglets with acute diarrhea, we explored the possible interactions between PEDV and other less reported pathogens. PEDV coinfection with porcine kobuvirus (PKV) was detected in 36.4% (27/74) of samples. Full genomes from porcine coronavirus and kobuvirus were obtained, as was a partial porcine sapovirus genome (PSaV). The phylogenetic results show the clustering of these strains corresponding to the geographical relationship. To our knowledge, this is the first full genome and isolation report for porcine kobuvirus in México, as well as the first phylogenetic analysis for porcine sapovirus in the country. The NGS approach provides a better perspective of circulating viruses and other pathogens in affected production units.
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Coinfección/virología , Infecciones por Coronavirus/virología , Kobuvirus/genética , Kobuvirus/aislamiento & purificación , Virus de la Diarrea Epidémica Porcina/genética , Virus de la Diarrea Epidémica Porcina/aislamiento & purificación , Animales , Coinfección/epidemiología , Infecciones por Coronavirus/epidemiología , Diarrea/virología , Heces/virología , Genoma Viral , Kobuvirus/clasificación , México/epidemiología , Técnicas de Diagnóstico Molecular , Filogenia , Virus de la Diarrea Epidémica Porcina/clasificación , Sapovirus/genética , Análisis de Secuencia , Porcinos , Enfermedades de los Porcinos/virologíaRESUMEN
INTRODUCTION AND OBJECTIVES: Cases of viral hepatitis reported in Mexico are typically identified as hepatitis A, B and C. However, unspecified cases are reported annually. Hepatitis E virus (HEV) is an emergent agent that causes a self-limiting infection that can evolve to chronic in immunosuppressed individuals. In Mexico, HEV genotype 2 is considered endemic, though it's the prevalence is not well known. Therefore, the present study was designed to determine the prevalence of HEV among patients at the "Hospital Infantil de Mexico Federico Gomez". MATERIALS AND METHODS: The study included 99 patients, anti-HEV antibody (IgG and IgM) were detected by indirect ELISA and viral genome was identified using RT-PCR technique. Two PCR products of positive cases were sequenced. RESULTS: ELISA results were positive in 3% and 6%, for IgG and IgM respectively, 54.5% prevalence was found by PCR. Low lymphocyte count (p<0.05) and malnutrition (p<0.005) were significant factors for high PCR prevalence and could increase the possibility of infection. Two samples were sequenced and confirmed the presence of HEV genotype 3. CONCLUSIONS: This report reveals the incidence of HEV in pediatric patients in Mexico. Moreover, the identification of HEV genotype 3 in human samples suggests a potential zoonotic risk that requires further research.
Asunto(s)
Virus de la Hepatitis E/genética , Hepatitis E/epidemiología , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Niño , Estudios Transversales , ADN Viral/sangre , Femenino , Genoma Viral/genética , Genotipo , Hepatitis A , Anticuerpos de Hepatitis A/sangre , Anticuerpos Antihepatitis , Anticuerpos contra la Hepatitis B/sangre , Anticuerpos contra la Hepatitis C/sangre , Hepatitis E/sangre , Hepatitis E/inmunología , Hepatitis E/virología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Estudios Longitudinales , Masculino , México/epidemiología , ARN Viral/sangre , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estudios Seroepidemiológicos , Proteínas Virales/genéticaRESUMEN
Mosquito-borne flaviviruses (MBFVs) are of public and animal health concern because they cause millions of human deaths annually and impact domestic animals and wildlife globally. MBFVs are phylogenetically divided into two clades, one is transmitted by Aedes mosquitoes (Ae-MBFVs) associated with mammals and the other by Culex mosquitoes (Cx-MBFVs) associated with birds. However, this assumption has not been evaluated. Here, we synthesized 79 published reports of MBFVs from wild mammals, estimating their host. Then, we tested whether the host specificity was biased to sampling and investigation efforts or to phylogenetic relationships using a viral phylogenetic tree drawn from analyzing whole flavivirus genomes obtained in GenBank. We found in total 18 flaviviruses, nine related to Aedes spp. and nine to Culex spp. infecting 129 mammal species. Thus, this supports that vectors are transmitting MBFV across available host clades and that ornithophilic mosquitoes are readily infecting mammals. Although most of the mosquito species are generalists in their host-feeding preferences, we also found a certain degree of MBFV's specificity, as most of them infect closely related mammal species. The present study integrates knowledge regarding MBFVs, and it may help to understand their transmission dynamics between viruses, vectors, and mammal hosts.
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Interacciones Microbiota-Huesped/inmunología , Especificidad del Huésped/genética , Especificidad del Huésped/inmunología , Mosquitos Vectores/virología , Fiebre del Nilo Occidental/inmunología , Fiebre del Nilo Occidental/transmisión , Virus del Nilo Occidental/aislamiento & purificación , Aedes/virología , Animales , Animales Domésticos/virología , Culex/virología , Interacciones Microbiota-Huesped/genética , Mamíferos/genética , Mamíferos/virologíaRESUMEN
Hepatitis E virus produces an emerging health problem, knowledge about epidemiology of hepatitis E virus infections in the USA and Latin America is still limited. The wide-ranging clinical manifestations lead to an extensive underestimation of the global seroprevalence. Clinical and diagnostic accuracy are critical to improve patient management.
Asunto(s)
Hepatitis E/epidemiología , Infecciones Asintomáticas/epidemiología , Genotipo , Hepatitis E/virología , Virus de la Hepatitis E/genética , Humanos , América Latina/epidemiología , México/epidemiología , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Hepatitis E virus (HEV) infection is one of the most common causes of acute liver diseases in humans worldwide. In developing countries, HEV is commonly associated with waterborne outbreaks. Conversely, in industrialized countries, HEV infection is often associated with travel to endemic regions or ingestion of contaminated animal products. Limited information on both, human and animal HEV infection in Mexico is available. As a consequence, the distribution of the virus in the country is largely unknown. Here, we assessed the seroprevalence of HEV among swine in different geographical regions in Mexico. METHODS: Seroprevalence of anti-HEV antibodies in swine herds in Mexico was evaluated in a representative sample including 945 pig serum specimens from different regions of the country using a commercial enzyme-linked immunosorbent assay (ELISA). RESULTS: The overall prevalence of anti-HEV antibodies in swine was 59.4%. The northern region of Mexico exhibited the highest seroprevalence in the country (86.6%), while the central and southern regions in Mexico showed lower seroprevalence, 42.7% and 51.5%, respectively. CONCLUSIONS: In Mexico, HEV seroprevalence in swine is high. Importantly, northern Mexico showed the highest seroprevalence in the country. Thus, further studies are required to identify the risk factors contributing to HEV transmission among pigs in the country. Assessment of HEV human infection in the context of viral transmission in swine is required to better understand the epidemiology of hepatitis E in Mexico.
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Anticuerpos Antivirales/sangre , Hepatitis E/veterinaria , Enfermedades de los Porcinos/virología , Animales , Hepatitis E/sangre , Hepatitis E/epidemiología , Hepatitis E/inmunología , México/epidemiología , Oportunidad Relativa , Estudios Seroepidemiológicos , Porcinos , Enfermedades de los Porcinos/epidemiología , Enfermedades de los Porcinos/inmunologíaRESUMEN
BACKGROUND: Interest in porcine epidemic diarrhea has grown since the 2013 outbreak in the United States caused major losses, with mortality rates up to 100 % in suckling piglets. In Mexico, an outbreak of porcine epidemic diarrhea, characterized by 100 % mortality in piglets, began in March 2014 in the State of Mexico. METHODS: The aim of this study was to confirm and identify porcine epidemic diarrhea virus (PEDV) in samples from piglets with suggestive clinical signs using virological, histological, and molecular techniques. Necropsy was performed on 13 piglets from two litters with initial and advanced clinical signs. Suggestive lesions of acute infection with PEDV were detected in histological sections of the small and large bowels; specifically, multiple virus particles with visible crown-shaped projections were observed using electron microscopy and negative staining. Viral isolation was performed in Vero cells with trypsin. Infection was monitored by observation of cytopathic effect, and titration was determined by TCID50/ml. The presence of the PEDV in cultures and clinical samples was confirmed by RT-PCR amplification and sequencing of a 651-bp segment of the S glycoprotein gene, as well as a 681-bp matrix protein gene. RESULTS: The nucleotide sequence analysis of the Mexican isolates showed marked homology to viruses that circulated in 2013 in Colorado, USA. CONCLUSIONS: In this paper we confirm the isolation and characterization of PEDV from animals with early and advanced clinical signs.
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Infecciones por Coronavirus/veterinaria , Brotes de Enfermedades/veterinaria , Virus de la Diarrea Epidémica Porcina/aislamiento & purificación , Enfermedades de los Porcinos/virología , Animales , Chlorocebus aethiops , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , México/epidemiología , Virus de la Diarrea Epidémica Porcina/ultraestructura , Reacción en Cadena en Tiempo Real de la Polimerasa/veterinaria , Porcinos , Enfermedades de los Porcinos/epidemiología , Enfermedades de los Porcinos/patología , Células VeroRESUMEN
West Nile virus (WNV) in the Americas is thought to be transported at large spatial scales by migratory birds and locally spread and amplified by resident birds. Local processes, including interspecific interactions and dominance of passerine species recognized as competent reservoirs, may boost infection and maintain endemic cycles. Change in species composition has been recognized as an important driver for infection dynamics. Due to migration and changes in species diversity and composition in wintering grounds, changes in infection prevalence are expected. To these changes, we used PCR to estimate the prevalence of WNV in wild resident birds during the dry and rainy seasons of 2012 in Yucatan, Mexico. Serum samples were obtained from 104 wild birds, belonging to six orders and 35 species. We detected WNV in 14 resident birds, representing 11 species and three orders. Prevalences by order was Passeriformes (27%), Columbiformes (6%), and Piciformes (33%). Resident birds positive to WNV from Yucatan may be indicative of local virus circulation and evidence of past virus transmission activity.
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Enfermedades de las Aves/epidemiología , Columbiformes , Passeriformes , Fiebre del Nilo Occidental/veterinaria , Migración Animal , Animales , Anticuerpos Antivirales/sangre , Enfermedades de las Aves/transmisión , Aves , Reservorios de Enfermedades , Ecosistema , Enfermedades Endémicas/veterinaria , México/epidemiología , Prevalencia , ARN Viral/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estaciones del Año , Fiebre del Nilo Occidental/epidemiología , Fiebre del Nilo Occidental/transmisión , Virus del Nilo Occidental/genética , Virus del Nilo Occidental/inmunologíaRESUMEN
Research on oncolytic viruses has mostly been directed towards the treatment of solid tumors, which has yielded limited information regarding their activity in hematological cancer. It has also been directed towards the treatment of humans, yet veterinary medicine may also benefit. Several strains of the Newcastle disease virus (NDV) have been used as oncolytics in vitro and in a number of in vivo experiments. We studied the cytolytic effect of NDV-MLS, a low virulence attenuated lentogenic strain, on a human large B-cell lymphoma cell line (SU-DHL-4), as well as on primary canine-derived B-cell lymphoma cells, and compared them to healthy peripheral blood mononuclear cells (PBMC) from both humans and dogs. NDV-MLS reduced cell survival in both human (42% ± 5%) and dog (34% ± 12%) lymphoma cells as compared to untreated controls. No significant effect on PBMC was seen. Cell death involved apoptosis as documented by flow-cytometry. NDV-MLS infections of malignant lymphoma tumors in vivo in dogs were confirmed by electron microscopy. Early (24 h) biodistribution of intravenous injection of 1 × 10(12) TCID50 (tissue culture infective dose) in a dog with T-cell lymphoma showed viral localization only in the kidney, the salivary gland, the lung and the stomach by immunohistochemistry and/or endpoint PCR. We conclude that NDV-MLS may be a promising agent for the treatment of lymphomas. Future research is needed to elucidate the optimal therapeutic regimen and establish appropriate biosafety measures.
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Enfermedades de los Perros/terapia , Linfoma/terapia , Linfoma/veterinaria , Virus de la Enfermedad de Newcastle/fisiología , Viroterapia Oncolítica , Virus Oncolíticos/fisiología , Animales , Apoptosis , Supervivencia Celular , Enfermedades de los Perros/fisiopatología , Perros , Humanos , Linfoma/fisiopatología , Virus de la Enfermedad de Newcastle/genética , Virus Oncolíticos/genéticaRESUMEN
The bovine respiratory syncytial virus (BRSV) is an enveloped, negative sense, single-stranded RNA virus belonging to the pneumovirus genus within the family Paramyxoviridae. BRSV has been recognized as a major cause of respiratory disease in young calves since the early 1970s. The analysis of BRSV infection was originally hampered by its characteristic lability and poor growth in vitro. However, the advent of numerous immunological and molecular methods has facilitated the study of BRSV enormously. The knowledge gained from these studies has also provided the opportunity to develop safe, stable, attenuated virus vaccine candidates. Nonetheless, many aspects of the epidemiology, molecular epidemiology and evolution of the virus are still not fully understood. The natural course of infection is rather complex and further complicates diagnosis, treatment and the implementation of preventive measures aimed to control the disease. Therefore, understanding the mechanisms by which BRSV is able to establish infection is needed to prevent viral and disease spread. This review discusses important information regarding the epidemiology and molecular epidemiology of BRSV worldwide, and it highlights the importance of viral evolution in virus transmission.
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Enfermedades de los Bovinos/epidemiología , Enfermedades de los Bovinos/virología , Epidemiología Molecular , Infecciones por Virus Sincitial Respiratorio/veterinaria , Virus Sincitial Respiratorio Bovino/clasificación , Virus Sincitial Respiratorio Bovino/aislamiento & purificación , Animales , Bovinos , Infecciones por Virus Sincitial Respiratorio/epidemiología , Virus Sincitial Respiratorio Bovino/genéticaRESUMEN
To persist, a virus must co-exist with the host that it infects, thus allowing the virus to survive and to subvert the programmed cell death of the host. In this study, we investigated whether the intrinsic pathway of the apoptotic process is suppressed in a previously reported macrophage cell line persistently infected with respiratory syncytial virus (RSV). To this end, after using staurosporine to induce apoptosis, we determined cell viability and the degree of annexin staining and DNA fragmentation between infected and mock-infected cells. RSV persistence leads to a subversion of apoptosis; whereas in mock-infected macrophages, apoptosis was evident. The cellular apoptotic pathway involve was searched by determining the activities of caspases and the expression of anti-apoptotic proteins. Although caspases-3 and -9 were expressed, their activities were altered; the activity of caspase-3 was reduced and that of caspase-9 could not be detected. Expression of anti-apoptotic proteins Bcl-2, Bcl-X, and XIAP was enhanced, with Bcl-X and XIAP being regulated post-transcriptionally; the induction of the anti-apoptotic factors and the reduced caspases activities might account for the subversion of apoptosis. The data implies that in our viral persistence model an anti-apoptotic program is induced relating alterations of caspases-3 and -9 activity and expression of anti-apoptotic proteins, suggesting that the intrinsic pathway is suppressed. These findings are of importance for understanding the intracellular genes involved in subversion of apoptosis by RSV persistence in macrophages.
Asunto(s)
Apoptosis , Evasión Inmune , Macrófagos/inmunología , Macrófagos/virología , Virus Sincitiales Respiratorios/inmunología , Virus Sincitiales Respiratorios/patogenicidad , Animales , Anexinas/análisis , Proteínas Reguladoras de la Apoptosis/metabolismo , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN , Ratones , Estaurosporina/toxicidad , Regulación hacia ArribaRESUMEN
Treatment of P388D1, a macrophage-like cell line, with staurosporine triggered apoptosis through the activation of caspase-9 and caspase-3. Unexpected effects of staurosporine on the induction of apoptosis were the activation of caspase-8, and an increase of the levels of TNF-alpha. The increased TNF-alpha levels led to activation of caspase-8 by an autocrine effect via the TNF receptor expressed by the P388D1 macrophages. In contrast, P388D1 macrophages that either had been exposed to UV light or treated with dexamethasone did not undergo apoptosis.