The effect of baricitinib on pSTAT3 levels in IL-6- or IL-15-stimulated PBMCs isolated from patients with SLE

Szebeni, Gábor and Gémes, Nikolett and Neuperger, Patricia and Szabó, Enikő and Balog, József Ágoston and Honfi, Dániel György and Balog, Attila and Toldi, Gergely (2025) The effect of baricitinib on pSTAT3 levels in IL-6- or IL-15-stimulated PBMCs isolated from patients with SLE. FRONTIERS IN IMMUNOLOGY, 16. ISSN 1664-3224

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Abstract

Introduction: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease marked by multi-organ inflammation. Its pathogenesis involves profound T-cell dysfunction, autoreactive B-cell activation, impaired CD8+ T-cell responses, myeloid cell abnormalities, and dysregulated cytokine secretion. Central to cytokine-driven immune activation is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. Baricitinib, a selective oral JAK1/2 inhibitor approved for rheumatoid arthritis, has been extensively studied in SLE.Methods: We aimed to investigate STAT3 phosphorylation in CD4+ and CD8+ T cells and CD11b+ myeloid cells from patients with SLE using single-cell flow cytometry of peripheral blood mononuclear cells (PBMCs) stimulated ex vivo with interleukin-6 (IL-6) or IL-15. We quantified pSTAT3 induction and assessed the inhibitory effect of baricitinib.Results: Despite long-term immunomodulators, significant STAT3 activation was observed in T cells and myeloid cells upon IL-6 or IL-15 stimulation in patients with SLE. Baricitinib effectively inhibited STAT3 phosphorylation in these cell types, though its inhibitory effect was notably weaker following IL-15 stimulation compared to IL-6. Notably, baricitinib did not affect the proportion of interferon-γ (IFN-γ)- or IL-17-expressing cells.Conclusion: These findings highlight the cell-type and cytokine-specific effects of baricitinib and demonstrate its capacity to dampen IL-6- and IL-15-mediated STAT3 activation in key immune cell subsets. Our results support a precision medicine approach to JAK inhibition in SLE and reinforce the potential of baricitinib in modulating key inflammatory pathways.

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