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1.
Cytokine ; 161: 156057, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36208532

RESUMEN

During inflammation, cellular glucose uptake and glycolysis are upregulated to meet an increased energy demand. For example, keratinocyte glycolysis is essential for progression of psoriasis. Therefore, understanding the regulation of glucose metabolism in keratinocytes is of importance. Here, we show that the pro-inflammatory cytokines IFNγ and TNF together rapidly induce glucose uptake, glycolysis, and glycolytic capacity in cultured keratinocytes. Furthermore, we found that acute IFNγ and TNF stimulation induces glucose transporter 4 (GLUT4) translocation to the plasma membrane and engages AMPK-dependent intracellular signaling. Together, these findings suggest acute cytokine-induced glucose metabolism in keratinocytes could contribute to inflammation in psoriatic disease, and that GLUT4 is involved in these processes.


Asunto(s)
Citocinas , Queratinocitos , Humanos , Citocinas/metabolismo , Queratinocitos/metabolismo , Glucosa/metabolismo , Glucólisis , Inflamación/metabolismo
2.
Arthritis Rheumatol ; 75(2): 220-231, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36577442

RESUMEN

OBJECTIVE: We undertook this study to examine the functional basis for epistasis between endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 in experimental spondyloarthritis (SpA). METHODS: ERAP1-knockout rats were created using genome editing and bred with HLA-B27/human ß2 -microglobulin-transgenic (HLA-B27-Tg) rats and HLA-B7-Tg rats. The effects of ERAP1 deficiency on HLA allotypes were determined using immunoprecipitation and immunoblotting, flow cytometry, allogeneic T cell proliferation assays, and gene expression analyses. Animals were examined for clinical features of disease, and tissue was assessed by histology. RESULTS: ERAP1 deficiency increased the ratio of folded to unfolded (ß2 m-free) HLA-B27 heavy chains, while having the opposite effect on HLA-B7. Furthermore, in rats with ERAP1 deficiency, HLA-B27 misfolding was reduced, while free HLA-B27 heavy chain dimers on the cell surface and monomers were increased. The effects of ERAP1 deficiency persisted during up-regulation of HLA-B27 and led to a reduction in endoplasmic reticulum stress. ERAP1 deficiency reduced the prevalence of arthritis in HLA-B27-Tg rats by two-thirds without reducing gastrointestinal inflammation. Dendritic cell abnormalities attributed to the presence of HLA-B27, including reduced allogeneic T cell stimulation and loss of CD103-positive/major histocompatibility complex class II-positive cells, were not rescued by ERAP1 deficiency, while excess Il23a up-regulation was mitigated. CONCLUSION: ERAP1 deficiency reduced HLA-B27 misfolding and improved folding while having opposing effects on HLA-B7. The finding that HLA-B27-Tg rats had partial protection against SpA in this study is consistent with genetic evidence that loss-of-function and/or reduced expression of ERAP1 reduces the risk of ankylosing spondylitis. Functional studies support the concept that the effects of ERAP1 on HLA-B27 and SpA may be a consequence of how peptides affect the biology of this allotype rather than their role as antigenic determinants.


Asunto(s)
Antígeno HLA-B27 , Espondilitis Anquilosante , Animales , Humanos , Ratas , Aminopeptidasas/genética , Aminopeptidasas/metabolismo , Retículo Endoplásmico/metabolismo , Antígeno HLA-B27/genética , Antígeno HLA-B27/metabolismo , Antígeno HLA-B7 , Antígenos de Histocompatibilidad Menor/genética , Espondilitis Anquilosante/genética , Artritis/genética , Artritis/metabolismo
3.
Semin Immunopathol ; 43(2): 235-243, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33481054

RESUMEN

Establishing a clear role for HLA-B*27 in the pathogenesis of spondyloarthritis continues to be challenging. Aberrant properties of the heavy chain as well as a potential role presenting arthritogenic peptides continue to be pursued as plausible mechanisms. Recent studies implicate HLA-B*27 in aberrant bone formation. An unanticipated cell surface interaction between HLA-B*27 and the bone morphogenetic protein pathway receptor subunit ALK2 may augment TGFß superfamily signaling pathways, increasing responsiveness to Activin A and TGFß. This has the potential to increase bone formation as well as Th17 T cell development, presenting an attractive model to explain several aspects of axial and peripheral spondyloarthritis. In a separate study, intracellular effects of misfolded HLA-B*27 implicate this mechanism in increased osteoblast mineralization and bone formation. HLA-B*27 expression in early osteoblasts activates unfolded protein response-mediated X-box binding protein-1 mRNA splicing and induction of the retinoic acid receptor-ß gene, with downstream increases in expression of tissue non-specific alkaline phosphatase. Increased TNAP expression in osteoblasts was linked to increased mineralization in vitro and bone formation in vivo. In the ongoing search for evidence of arthritogenic peptides, high-throughput TCR (T cell receptor) sequencing has provided evidence for reduced clonal expansion and increased TCR diversity in ankylosing spondylitis. In addition to two common CD8+ TCR sequences identified in one study, similar CD8 and CD4 TCR motifs were found in another study. Further work will be needed to shed light on the nature of the peptide-HLA class I complex recognized by these T cells and its role in disease.


Asunto(s)
Espondiloartritis , Espondilitis Anquilosante , Antígeno HLA-B27/genética , Humanos , Receptores de Antígenos de Linfocitos T , Espondiloartritis/genética , Espondilitis Anquilosante/genética , Células Th17
4.
PLoS One ; 9(10): e108920, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25302610

RESUMEN

Increased marrow medullary adipogenesis and an associated decrease in bone mineral density, usually observed in elderly individuals, is a common characteristic in senile osteoporosis. In this study we investigated whether cells of the medullary adipocyte lineage have the potential to directly support the formation of osteoclasts, whose activity in bone leads to bone degradation. An in vitro mesenchymal stem cell (MSC)-derived medullary adipocyte lineage culture model was used to study the expression of the important osteoclast mediators RANKL, M-CSF, SDF-1, and OPG. We further assessed whether adipocytes at a specific developmental stage were capable of supporting osteoclast-like cell formation in culture. In vitro MSC-derived medullary adipocytes showed an mRNA and protein expression profile of M-CSF, RANKL, and OPG that was dependent on its developmental/metabolic stage. Furthermore, RANKL expression was observed in MSC-derived adipocytes that were at a distinct lineage stage and these cells were also capable of supporting osteoclast-like cell formation in co-cultures with peripheral blood mononuclear cells. These results suggest a connection between medullary adipocytes and osteoclast formation in vivo and may have major significance in regards to the mechanisms of decreased bone density in senile osteoporosis.


Asunto(s)
Adipocitos/citología , Células de la Médula Ósea/citología , Células Madre Mesenquimatosas/citología , Osteoclastos/citología , Adipocitos/metabolismo , Adipogénesis , Células de la Médula Ósea/metabolismo , Células Cultivadas , Quimiocina CXCL12/análisis , Quimiocina CXCL12/genética , Técnicas de Cocultivo , Regulación del Desarrollo de la Expresión Génica , Humanos , Factor Estimulante de Colonias de Macrófagos/análisis , Factor Estimulante de Colonias de Macrófagos/genética , Células Madre Mesenquimatosas/metabolismo , Osteoclastos/metabolismo , Osteoprotegerina/análisis , Osteoprotegerina/genética , Ligando RANK/análisis , Ligando RANK/genética , ARN Mensajero/análisis , ARN Mensajero/genética
5.
Genome Biol ; 5(12): 253, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15575979

RESUMEN

The Janus kinase (Jak) family is one of ten recognized families of non-receptor tyrosine kinases. Mammals have four members of this family, Jak1, Jak2, Jak3 and Tyrosine kinase 2 (Tyk2). Birds, fish and insects also have Jaks. Each protein has a kinase domain and a catalytically inactive pseudo-kinase domain, and they each bind cytokine receptors through amino-terminal FERM (Band-4.1, ezrin, radixin, moesin) domains. Upon binding of cytokines to their receptors, Jaks are activated and phosphorylate the receptors, creating docking sites for signaling molecules, especially members of the signal transducer and activator of transcription (Stat) family. Mutations of the Drosophila Jak (Hopscotch) have revealed developmental defects, and constitutive activation of Jaks in flies and humans is associated with leukemia-like syndromes. Through the generation of Jak-deficient cell lines and gene-targeted mice, the essential, nonredundant functions of Jaks in cytokine signaling have been established. Importantly, deficiency of Jak3 is the basis of human autosomal recessive severe combined immunodeficiency (SCID); accordingly, a selective Jak3 inhibitor has been developed, forming a new class of immunosuppressive drugs.


Asunto(s)
Proteínas Tirosina Quinasas/metabolismo , Animales , Evolución Biológica , Humanos , Conformación Proteica , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/genética
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