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Contribution of Janus-Kinase/Signal Transduction Activator of Transcription Pathway in the Pathogenesis of Vasculitis: A Possible Treatment Target in the Upcoming Future.

ABSTRACT: Janus-kinase (JAK) and signal transduction activator of transcription (STAT) signal transduction pathway is involved in a wide range of physiological and pathological processes, including in the pathogenesis of several autoimmune diseases. Data supporting the role of JAK/STAT in the development of vasculitis are limited and mostly focused on large vessel vasculitis and Behçet's disease. In this review, we provide a thorough picture of currently available evidence on the topic, gathered from in vitro experiments, animal models and human real-life data, analyzing the rationale for the use of JAK inhibitors for the management of vasculitis. Overall, despite a very strong biological and pathogenic basis, data are too few to recommend this therapeutic approach, beyond very severe and refractory forms of vasculitis. However, for the same reasons, a strong scientific effort in this direction is indeed worthwhile.

SUBMITTER: Bursi R

PROVIDER: S-EPMC8039124 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Contribution of Janus-Kinase/Signal Transduction Activator of Transcription Pathway in the Pathogenesis of Vasculitis: A Possible Treatment Target in the Upcoming Future.

Bursi Roberto R Cafaro Giacomo G Perricone Carlo C Riccucci Ilenia I Calvacchi Santina S Gerli Roberto R Bartoloni Elena E

Frontiers in pharmacology 20210329

Janus-kinase (JAK) and signal transduction activator of transcription (STAT) signal transduction pathway is involved in a wide range of physiological and pathological processes, including in the pathogenesis of several autoimmune diseases. Data supporting the role of JAK/STAT in the development of vasculitis are limited and mostly focused on large vessel vasculitis and Behçet's disease. In this review, we provide a thorough picture of currently available evidence on the topic, gathered from <i>i ...[more]

PMID: 33854436

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Project description:BackgroundIn recent years, the incidence of pneumonia has been increasing, which is the main cause of death and morbidity of children and the elderly in the world. Slfn5 is implicated in multiple cancers, and Slfn5 promotes epithelial-mesenchymal transition and metastasis in lung cancer. However, the influences of Slfn5 in pneumonia have not yet been completely cleared. Herein, we aimed to explore the underlying effects and regulatory mechanisms of Slfn5 in lipopolysaccharide (LPS)-induced pneumonia in mice and A549 cells.MethodsMice were intratracheally administered 5 mg/kg LPS to construct pneumonia model. In vitro, A549 cells were treated with 10 µg/mL LPS to construct cellular pneumonia model. Slfn5 expression was detected using immunohistochemistry and western blotting. Haematoxylin and eosin staining, TUNEL (terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate‑biotin nick end‑labelling), and western blotting were performed to assess pathological injury and inflammation. MTT [3(4,5‑dimethyl‑2‑thiazolyl)‑2,5‑diphenyl‑2‑H‑tetrazolium bromide], flow cytometry, and enzyme-linked immunosorbent assay analysis were performed to analyze cell viability, apoptosis, and inflammation. Gene set enrichment analysis was performed to explore the mechanism of Slfn5 in pneumonia.ResultsSlfn5 expression was upregulated in LPS-induced pneumonia in mice and A549 cells. In mice, knockdown of Slfn5 weakened LPS-induced lung injury and inflammation and decreased the expression of p-JAK2, p-JAK3, and p-STAT3. In LPS-stimulated A549 cells, downregulation of Slfn5 expression increased and Slfn5 overexpression decreased cell viability. Downregulation of Slfn5 expression decreased and Slfn5 overexpression increased cell apoptosis, inflammation and the expression of p-JAK2, p-JAK3, and p-STAT3. AG490, an inhibitor of the JAK/STAT pathway, reversed the damaging effects of Slfn5 overexpression.ConclusionsIn the LPS-induced pneumonia model, Slfn5 knockdown alleviated LPS-induced lung injury by regulating the JAK/STAT pathway.

Project description:OBJECTIVE:Glomerular mesangial expansion and podocyte loss are important early features of diabetic nephropathy, whereas tubulointerstitial injury and fibrosis are critical for progression of diabetic nephropathy to kidney failure. Therefore, we analyzed the expression of genes in glomeruli and tubulointerstitium in kidney biopsies from diabetic nephropathy patients to identify pathways that may be activated in humans but not in murine models of diabetic nephropathy that fail to progress to glomerulosclerosis, tubulointerstitial fibrosis, and kidney failure. RESEARCH DESIGN AND METHODS:Kidney biopsies were obtained from 74 patients (control subjects, early and progressive type 2 diabetic nephropathy). Glomerular and tubulointerstitial mRNAs were microarrayed, followed by bioinformatics analyses. Gene expression changes were confirmed by real-time RT-PCR and immunohistological staining. Samples from db/db C57BLKS and streptozotocin-induced DBA/2J mice, commonly studied murine models of diabetic nephropathy, were analyzed. RESULTS:In human glomeruli and tubulointerstitial samples, the Janus kinase (Jak)-signal transducer and activator of transcription (Stat) pathway was highly and significantly regulated. Jak-1, -2, and -3 as well as Stat-1 and -3 were expressed at higher levels in patients with diabetic nephropathy than in control subjects. The estimated glomerular filtration rate significantly correlated with tubulointerstitial Jak-1, -2, and -3 and Stat-1 expression (R(2) = 0.30-0.44). Immunohistochemistry found strong Jak-2 staining in glomerular and tubulointerstitial compartments in diabetic nephropathy compared with control subjects. In contrast, there was little or no increase in expression of Jak/Stat genes in the db/db C57BLKS or diabetic DBA/2J mice. CONCLUSIONS:These data suggest a direct relationship between tubulointerstitial Jak/Stat expression and progression of kidney failure in patients with type 2 diabetic nephropathy and distinguish progressive human diabetic nephropathy from nonprogressive murine diabetic nephropathy.

Dataset Information

Contribution of Janus-Kinase/Signal Transduction Activator of Transcription Pathway in the Pathogenesis of Vasculitis: A Possible Treatment Target in the Upcoming Future.

Publications

Contribution of Janus-Kinase/Signal Transduction Activator of Transcription Pathway in the Pathogenesis of Vasculitis: A Possible Treatment Target in the Upcoming Future.

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