RESUMEN
This review emphasizes how translation from bench research to clinical knowledge and vice versa has resulted in considerable progress in understanding the immunopathogenesis of psoriasis. First, the journey in understanding the pathogenic mechanisms behind psoriasis is described. The roles of different components of the adaptive and innate immune systems involved in driving the inflammatory response are explained. Discovery of new immune pathways i.e. the IL23/Th17 axis and its subsequent impact on the development of novel biological therapies is highlighted. Identification of potential targets warranting further research for future therapeutic development are also discussed (AU)
Esta revisión se centra en el notable progreso que ha generado la aplicación de la investigación básica al conocimiento clínico, y viceversa, en la comprensión de la inmunopatogenia de la psoriasis. Se describe la trayectoria en el conocimiento de los mecanismos patogénicos de la psoriasis; se explican los roles de los diferentes componentes de los sistemas inmunológicos, adaptativo e innato, implicados en la respuesta inflamatoria; se destaca el descubrimiento de nuevas vías inmunológicas, como por ejemplo el eje Il23/Th17 y su posterior impacto en el desarrollo de terapias biológicas novedosas y también se discute la identificación de potenciales dianas que justifican una investigación adicional para el desarrollo terapéutico futuro (AU)
Asunto(s)
Humanos , Psoriasis/inmunología , Inmunidad Innata/inmunología , Psoriasis/etiología , Linfocitos T/inmunología , Psoriasis/genética , Antígenos HLA-D/genética , Interleucina-23/genética , Células Dendríticas/inmunologíaRESUMEN
This review emphasizes how translation from bench research to clinical knowledge and vice versa has resulted in considerable progress in understanding the immunopathogenesis of psoriasis. First, the journey in understanding the pathogenic mechanisms behind psoriasis is described. The roles of different components of the adaptive and innate immune systems involved in driving the inflammatory response are explained. Discovery of new immune pathways i.e. the IL23/Th17 axis and its subsequent impact on the development of novel biological therapies is highlighted. Identification of potential targets warranting further research for future therapeutic development are also discussed.
Asunto(s)
Psoriasis/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Interleucina-12/inmunología , Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
The mycotoxin, ochratoxin A (OTA), which is produced by Aspergillus and Penicillium subspecies, is frequently present in feedstuffs. Ochratoxin A exhibits a wide range of toxic activities including nephrotoxicity. However, the underlying molecular mechanisms of OTA-induced cellular nephrotoxicity have yet not been fully elucidated. Nrf2 is a basic leucine zipper transcriptional activator essential for the coordinated transcriptional induction of antioxidant and xenobiotic metabolizing enzymes in the kidney. Therefore, in the present study, the effects of OTA on the nuclear translocation and transactivation of the transcription factor Nrf2 as well as mRNA levels of Nrf2 target genes including glutathione-S-transferase and gamma-glutamylcysteinyl synthetase have been studied in cultured porcine kidney tubulus cells (LLC-PK1). Nrf2 was induced by sulforaphane, a well-known activator of this transcription factor. Ochratoxin A significantly decreased gamma-glutamylcysteinyl synthetase and glutathione-S-transferase mRNA levels in LLC-PK1 cells. Decreased mRNA levels of gamma-glutamylcysteinyl synthetase and glutathione-S-transferase were accompanied by a lowered nuclear translocation and transactivation of Nrf2. Furthermore, OTA also lowered Nrf2 mRNA levels. Current data indicate that OTA nephrotoxicity may be, at least partly, mediated by an Nrf2-dependent signal transduction pathway.
Asunto(s)
Túbulos Renales/citología , Túbulos Renales/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Ocratoxinas/toxicidad , Animales , Línea Celular , Isotiocianatos , Túbulos Renales/metabolismo , Factor 2 Relacionado con NF-E2/genética , Reacción en Cadena de la Polimerasa/veterinaria , Sulfóxidos , Porcinos , Tiocianatos/farmacologíaRESUMEN
The chemokines CX3CL1/Fractalkine and CXCL16 are expressed as transmembrane molecules and can mediate cell-cell-adhesion. By proteolytic processing, CX3CL1 and CXCL16 are released from the cell surface by proteolytic shedding resulting in the generation of soluble chemoattractants. This ectodomain release is mediated by the alpha-secretase-like activity of the two disintegrins and metalloproteinases ADAM10 and ADAM17. Using CX3CL1 and CXCL16 constructs C-terminally fused to two Z-domains of Protein A (2Z-tag) we detect C-terminal fragments (CTFs) of both chemokines resulting from ADAM10-mediated cleavages at multiple sites as examined by inhibitor studies. Furthermore, inhibitor studies as well as genetic studies using presenilin 1/2-deficient cell lines suggest the involvement of gamma-secretase-but not beta-secretase-like activity in the processing of transmembrane chemokines. The combination of alpha- and gamma-secretase and proteasomal inhibitors points towards a sequential processing of transmembrane chemokines by first ADAM10 and then gamma-secretases and possible further degradation. This proteolytic processing cascade of transmembrane chemokines is similar to that described for Notch and E-cadherin where CTFs generated by gamma-secretase serve as intracellular signal transmitters.
