Investigating new roles of the ubiquitin proteasome system in cell death and innate immune signalling

Immune responses are a complex network of interactions between proteins in different cellular processes with multiple layers of regulation. In the present study, we explored the role of some regulators of the ubiquitination and proteasome systems in cell death and innate immune signalling pathways in macrophages. Initial studies focused on a form of regulated cell death termed necroptosis, a type of cell death mediated by the receptor-interacting protein kinases (RIP). RIP kinases are known to interact with E3 ubiquitin ligases Pellino proteins. Pellino 1 has recently been described to target RIP kinases and regulate necroptosis. Firstly, the roles of the E3 ubiquitin ligases Pellino 2 and Pellino 3 were studied. The findings demonstrated that neither of them regulates necroptosis induced by innate immunity triggers. Studies next characterised the role of TLR signalling pathways in the activation of hypoxia-inducible factor 1α (HIF-1α), a critical target of the ubiquitin/proteasome system. Interestingly, these studies revealed that some of the TLRs promote a faster migration form of HIF-1α of approximately 40kDa. The upregulation of the latter was mediated by the TLR adaptor protein TRIF. The role of proteasome and lysosome mediators on processing of full length 110kDa HIF-1α to this smaller form was also assessed. As part of these experimental approaches, an intriguing discovery was made showing that treatment of macrophages with the proteasome inhibitor MG132 induced high levels of the anti-inflammatory cytokine IL10. This effect was dependent on P38 MAPK pathway activation and phosphorylation of the transcription factor CREB. Similar results were seen with proteasome inhibitor Bortezomib which is used clinically in the treatment of multiple myeloma. This effect is interesting considering that IL10 is a growth factor for myeloma cells and some patients treated with Bortezomib develop a refractory response to treatment and progression of disease. Overall, the present research provides novel insights into the roles of some regulators of the ubiquitin and proteasome systems in cell death and inflammatory signalling in macrophages

Toll-like receptors in the pathogenesis of human B cell malignancies

Toll-like receptors (TLRs) are important players in B-cell activation, maturation and memory and may be involved in the pathogenesis of B-cell lymphomas. Accumulating studies show differential expression in this heterogeneous group of cancers. Stimulation with TLR specific ligands, or agonists of their ligands, leads to aberrant responses in the malignant B-cells. According to current data, TLRs can be implicated in malignant transformation, tumor progression and immune evasion processes. Most of the studies focused on multiple myeloma and chronic lymphocytic leukemia, but in the last decade the putative role of TLRs in other types of B-cell lymphomas has gained much interest. The aim of this review is to discuss recent findings on the role of TLRs in normal B cell functioning and their role in the pathogenesis of B-cell malignancies

Arginine and cancer : Implications in the regulation of antitumoral response

ABSTRACT: Recent findings support the potential role of arginine as a regulator of the immune response. Correlation between decreased arginine and decreased proliferation and activation of T lymphocytes has been described in liver transplantation, severe trauma, sepsis and cancer. Among the effects, decrease in the CD3z chain expression (activation signal in the T cell) has been described. Arginine is reduced in relation to the production of arginase 1 (ARG1) by myeloid suppressor cells. Two possible mechanisms have been postulated by which the increased activity of ARG1 could be acting on a tumor. The first is the reduction of lymphocyte proliferation and cell cycle arrest. The second is to promote tumor growth by transforming arginine in precursors of polyamines. We present in this article the main concepts on the role of arginine in antitumor response.RESUMEN: Los informes de la literatura apoyan el papel de la arginina como mecanismo regulador de la respuesta inmune. Se ha descrito la correlación entre disminución de la arginina y reducción de la proliferación y la activación de los linfocitos T en trasplante hepático, trauma grave, sepsis y cáncer. Entre los efectos se describen la disminución en la expresión de la cadena CD3z (traducción de la señal de activación en el linfocito T). La disminución de la arginina está relacionada con la producción de arginasa 1 (ARG1) por parte de las células mieloides supresoras. Se han propuesto dos posibles mecanismos por medio de los cuales el aumento de la actividad de ARG1 podría estar actuando en un proceso tumoral. El primero es la disminución de la proliferación de los linfocitos y el freno del ciclo celular. El segundo es promover el crecimiento tumoral al transformar la arginina en precursores de poliaminas. Se presentan en este artículo los principales conceptos del papel de la arginina en la respuesta antitumoral

Investigating new roles of the ubiquitin proteasome system in cell death and innate immune signalling

Immune responses are a complex network of interactions between proteins in different cellular processes with multiple layers of regulation. In the present study, we explored the role of some regulators of the ubiquitination and proteasome systems in cell death and innate immune signalling pathways in macrophages. Initial studies focused on a form of regulated cell death termed necroptosis, a type of cell death mediated by the receptor-interacting protein kinases (RIP). RIP kinases are known to interact with E3 ubiquitin ligases Pellino proteins. Pellino 1 has recently been described to target RIP kinases and regulate necroptosis. Firstly, the roles of the E3 ubiquitin ligases Pellino 2 and Pellino 3 were studied. The findings demonstrated that neither of them regulates necroptosis induced by innate immunity triggers. Studies next characterised the role of TLR signalling pathways in the activation of hypoxia-inducible factor 1α (HIF-1α), a critical target of the ubiquitin/proteasome system. Interestingly, these studies revealed that some of the TLRs promote a faster migration form of HIF-1α of approximately 40kDa. The upregulation of the latter was mediated by the TLR adaptor protein TRIF. The role of proteasome and lysosome mediators on processing of full length 110kDa HIF-1α to this smaller form was also assessed. As part of these experimental approaches, an intriguing discovery was made showing that treatment of macrophages with the proteasome inhibitor MG132 induced high levels of the anti-inflammatory cytokine IL10. This effect was dependent on P38 MAPK pathway activation and phosphorylation of the transcription factor CREB. Similar results were seen with proteasome inhibitor Bortezomib which is used clinically in the treatment of multiple myeloma. This effect is interesting considering that IL10 is a growth factor for myeloma cells and some patients treated with Bortezomib develop a refractory response to treatment and progression of disease. Overall, the present research provides novel insights into the roles of some regulators of the ubiquitin and proteasome systems in cell death and inflammatory signalling in macrophages

Investigating new roles of the ubiquitin proteasome system in cell death and innate immune signalling

Immune responses are a complex network of interactions between proteins in different cellular processes with multiple layers of regulation. In the present study, we explored the role of some regulators of the ubiquitination and proteasome systems in cell death and innate immune signalling pathways in macrophages. Initial studies focused on a form of regulated cell death termed necroptosis, a type of cell death mediated by the receptor-interacting protein kinases (RIP). RIP kinases are known to interact with E3 ubiquitin ligases Pellino proteins. Pellino 1 has recently been described to target RIP kinases and regulate necroptosis. Firstly, the roles of the E3 ubiquitin ligases Pellino 2 and Pellino 3 were studied. The findings demonstrated that neither of them regulates necroptosis induced by innate immunity triggers. Studies next characterised the role of TLR signalling pathways in the activation of hypoxia-inducible factor 1α (HIF-1α), a critical target of the ubiquitin/proteasome system. Interestingly, these studies revealed that some of the TLRs promote a faster migration form of HIF-1α of approximately 40kDa. The upregulation of the latter was mediated by the TLR adaptor protein TRIF. The role of proteasome and lysosome mediators on processing of full length 110kDa HIF-1α to this smaller form was also assessed. As part of these experimental approaches, an intriguing discovery was made showing that treatment of macrophages with the proteasome inhibitor MG132 induced high levels of the anti-inflammatory cytokine IL10. This effect was dependent on P38 MAPK pathway activation and phosphorylation of the transcription factor CREB. Similar results were seen with proteasome inhibitor Bortezomib which is used clinically in the treatment of multiple myeloma. This effect is interesting considering that IL10 is a growth factor for myeloma cells and some patients treated with Bortezomib develop a refractory response to treatment and progression of disease. Overall, the present research provides novel insights into the roles of some regulators of the ubiquitin and proteasome systems in cell death and inflammatory signalling in macrophages

Investigating new roles of the ubiquitin proteasome system in cell death and innate immune signalling

Immune responses are a complex network of interactions between proteins in different cellular processes with multiple layers of regulation. In the present study, we explored the role of some regulators of the ubiquitination and proteasome systems in cell death and innate immune signalling pathways in macrophages. Initial studies focused on a form of regulated cell death termed necroptosis, a type of cell death mediated by the receptor-interacting protein kinases (RIP). RIP kinases are known to interact with E3 ubiquitin ligases Pellino proteins. Pellino 1 has recently been described to target RIP kinases and regulate necroptosis. Firstly, the roles of the E3 ubiquitin ligases Pellino 2 and Pellino 3 were studied. The findings demonstrated that neither of them regulates necroptosis induced by innate immunity triggers. Studies next characterised the role of TLR signalling pathways in the activation of hypoxia-inducible factor 1α (HIF-1α), a critical target of the ubiquitin/proteasome system. Interestingly, these studies revealed that some of the TLRs promote a faster migration form of HIF-1α of approximately 40kDa. The upregulation of the latter was mediated by the TLR adaptor protein TRIF. The role of proteasome and lysosome mediators on processing of full length 110kDa HIF-1α to this smaller form was also assessed. As part of these experimental approaches, an intriguing discovery was made showing that treatment of macrophages with the proteasome inhibitor MG132 induced high levels of the anti-inflammatory cytokine IL10. This effect was dependent on P38 MAPK pathway activation and phosphorylation of the transcription factor CREB. Similar results were seen with proteasome inhibitor Bortezomib which is used clinically in the treatment of multiple myeloma. This effect is interesting considering that IL10 is a growth factor for myeloma cells and some patients treated with Bortezomib develop a refractory response to treatment and progression of disease. Overall, the present research provides novel insights into the roles of some regulators of the ubiquitin and proteasome systems in cell death and inflammatory signalling in macrophages

Arginine and cancer: Implications in the regulation of antitumoral response = Arginina y cáncer: implicaciones en la regulación de la respuesta antitumoral

Recent findings support the potential role of arginine as a regulator of the immune response. Correlation between decreased arginine and decreased proliferation and activation of T lymphocytes has been described in liver transplantation, severe trauma, sepsis and cancer. Among the effects, decrease in the CD3z chain expression (activation signal in the T cell) has been described. Arginine is reduced in relation to the production of arginase 1 (ARG1) by myeloid suppressor cells. Two possible mechanisms have been postulated by which the increased activity of ARG1 could be acting on a tumor. The first is the reduction of lymphocyte proliferation and cell cycle arrest. The second is to promote tumor growth by transforming arginine in precursors of polyamines. We present in this article the main concepts on the role of arginine in antitumor response

Coordinación óptima de relés de sobrecorriente usando Partículas Swarm

En este artículo se presenta una metodología que permite encontrar los parámetros de ajuste de los relés de sobrecorriente empleando un algoritmo basado en Partículas Swarm, con el fin de garantizar un mejor comportamiento de estos ante fallas en sistemas de potencia. El modelo matemático propuesto involucra en la función objetivo las restricciones operativas, por lo que este modelo queda solamente en función de los diales de los relés, simplificando de esta forma los cálculos durante el procedimiento. Para validar la metodología propuesta se emplea el sistema de distribución de la ciudad de Pereira, obteniendo resultados de gran calidad al compararlos con los encontrados con métodos convencionales

Las TIC como aporte pedagógico en el Aula Hospitalaria Pablito

In the present work, ICT’s were recognized as a pedagogue aide that favors the growing up of children of Pablito hospital; through an investigation where different reflective workshops were applied, which allowed to recognize the validity and relevance of ICT’s as a branch of social pedagogy, set with a professional practice that transversalizes three pedagogical projects by dynamizing the use of ICT’s for educational and training purposes, allowing children to continue with their educational training processes, obtaining positive results in the development of The whole process carried out This research was carried out throughout a methodological approach of participant observation, which displayed favorable results that allowed to reflect on the contribution of ICT’s as a pedagogical strategy, starting from the interaction with children and the intervention of educational agents under charge, which were part of the different activities carried outn in this researchEn el presente trabajo, se hizo un reconocimiento de las TIC como aporte pedagógico favoreciendo la formación de los niños del Aula hospitalaria Pablito, a través de una investigación donde se aplicaron diferentes talleres reflexivos, que permitieron reconocer la validez y pertinencia de las TIC en una rama de la pedagogía social, conjugada con una práctica Profesionalizante transversal a tres proyectos pedagógicos que dinamizaron el uso de las TIC con fines pedagógicos y formativos, permitiéndole a los niños continuar con sus procesos de formación educativa, obteniendo resultados positivos en el desarrollo de todo el proceso realizado. Esta investigación se llevó a cabo por medio de un enfoque metodológico de observación participante que arrojó resultados favorables que permitieron reflexionar acerca del aporte del TIC como estrategia pedagógica, a partir de la interacción con los niños y la intervención de agentes educativos a su cargo, que hicieron parte de las diferentes actividades de esta investigación

The Necrobiology of Mesenchymal Stromal Cells Affects Therapeutic Efficacy

Rapid progress is occurring in understanding the mechanisms underlying mesenchymal stromal cell (MSC)-based cell therapies (MSCT). However, the results of clinical trials, while demonstrating safety, have been varied in regard to efficacy. Recent data from different groups have shown profound and significant influences of the host inflammatory environment on MSCs delivered systemically or through organ-specific routes, for example intratracheal, with subsequent actions on potential MSC efficacies. Intriguingly in some models, it appears that dead or dying cells or subcellular particles derived from them, may contribute to therapeutic efficacy, at least in some circumstances. Thus, the broad cellular changes that accompany MSC death, autophagy, pre-apoptotic function, or indeed the host response to these processes may be essential to therapeutic efficacy. In this review, we summarize the existing literature concerning the necrobiology of MSCs and the available evidence that MSCs undergo autophagy, apoptosis, transfer mitochondria, or release subcellular particles with effector function in pathologic or inflammatory in vivo environments. Advances in understanding the role of immune effector cells in cell therapy, especially macrophages, suggest that the reprogramming of immunity associated with MSCT has a weighty influence on therapeutic efficacy. If correct, these data suggest novel approaches to enhancing the beneficial actions of MSCs that will vary with the inflammatory nature of different disease targets and may influence the choice between autologous or allogeneic or even xenogeneic cells as therapeutics