Article
Ex vivo efect of JAK inhibition on JAK‑STAT1 pathway hyperactivation in patients with dominant‑negative STAT3 mutations
Author/s | Blanco Lobo, Pilar
Guisado Hernández, Paloma Villaoslada, Isabel Felipe, Beatriz de Carreras, Carmen Rodriguez, Hector Olbrich, Peter |
Department | Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología |
Publication Date | 2022 |
Deposit Date | 2022-12-15 |
Published in |
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Abstract | Purpose STAT1 gain-of-function (GOF) and dominant-negative (DN) STAT3 syndromes share clinical manifestations includ ing infectious and infammatory manifestations. Targeted treatment with Janus-kinase (JAK) inhibitors shows ... Purpose STAT1 gain-of-function (GOF) and dominant-negative (DN) STAT3 syndromes share clinical manifestations includ ing infectious and infammatory manifestations. Targeted treatment with Janus-kinase (JAK) inhibitors shows promising results in treating STAT1 GOF-associated symptoms while management of DN STAT3 patients has been largely supportive. We here assessed the impact of ruxolitinib on the JAK-STAT1/3 pathway in DN STAT3 patients’ cells. Methods Using fow cytometry, immunoblot, qPCR, and ELISA techniques, we examined the levels of basal STAT1 and phosphorylated STAT1 (pSTAT1) of cells obtained from DN STAT3, STAT1 GOF patients, and healthy donors following stimulation with type I/II interferons (IFNs) or interleukin (IL)-6. We also describe the impact of ruxolitinib on cytokine induced STAT1 signaling in these patients. Results DN STAT3 and STAT1 GOF resulted in a similar phenotype characterized by increased STAT1 and pSTAT1 levels in response to IFNα (CD3+ cells) and IFNγ (CD14+ monocytes). STAT1-downstream gene expression and C-X-C motif chemokine 10 secretion were higher in most DN STAT3 patients upon stimulation compared to healthy controls. Ex vivo treatment with the JAK1/2-inhibitor ruxolitinib reduced cytokine responsiveness and normalized STAT1 phosphorylation in DN STAT3 and STAT1 GOF patient’ cells. In addition, ex vivo treatment was efective in modulating STAT1 downstream signaling in DN STAT3 patients. Conclusion In the absence of efective targeted treatment options for AD-HIES at present, modulation of the JAK/STAT1 pathway with JAK inhibitors may be further explored particularly in those AD-HIES patients with autoimmune and/or autoinfammatory manifestations. |
Funding agencies | Consejería de Salud de la Junta de Andalucía Agencia de Innovación y Desarrollo de Andalucía Instituto de Salud Carlos III |
Project ID. | SA0051/2020
PI-0184-2018 |
Citation | Blanco Lobo, P., Guisado Hernández, P., Villaoslada, I., Felipe, B.d., Carreras, C., Rodriguez, H. y Olbrich, P. (2022). Ex vivo efect of JAK inhibition on JAK‑STAT1 pathway hyperactivation in patients with dominant‑negative STAT3 mutations. Journal of Clinical Immunology, 42 (6), 1193-1204. https://doi.org/10.1007/s10875-022-01273-x. |
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