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Updated: Apr 30, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

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Blocking the janus-activated kinase pathway reduces tumor necrosis factor alpha-induced interleukin-18 bioactivity by

Hubert Marotte, Pei-Suen Tsou, Tatiana Fedorova

    Arthritis Research & Therapy
    |April 26, 2014
    PubMed
    Abstract

    Insights

    Blocking the janus-activated kinase (JAK) pathway reduces tumor necrosis factor-α (TNF)-induced interleukin-18 (IL-18) bioactivity by inhibiting caspase-1. This suggests JAK inhibition is a potential therapeutic strategy for rheumatoid arthritis (RA).

    Area of Science:

    • Immunology and Inflammation Research
    • Molecular Biology and Signaling Pathways

    Background:

    • Tumor necrosis factor-α (TNF) plays a key role in the inflammatory processes of rheumatoid arthritis (RA).
    • Interleukin-18 (IL-18) is a pro-inflammatory cytokine implicated in RA pathogenesis.
    • The janus-activated kinase (JAK) pathway is a critical signaling cascade involved in immune responses.

    Purpose of the Study:

    • To investigate the role of the JAK pathway in modulating TNF-induced IL-18 bioactivity.
    • To examine the impact of reducing caspase-1 function on TNF-induced IL-18 bioactivity.
    • To explore the potential of JAK inhibition as a therapeutic approach for RA.

    Main Methods:

    • Caspase-1 expression in RA synovial fibroblasts stimulated with TNF was analyzed using qRT-PCR and Western blot.
    • IL-18 levels and bioactivity were assessed via ELISA, immunofluorescence (IF), and functional assays with KG-1 cells.
    • The involvement of JAK and ERK1/2 pathways was determined using chemical signaling inhibitors.

    Main Results:

    • TNF significantly increased caspase-1 expression in RA synovial fibroblasts at the protein level.
    • Inhibition of the JAK pathway markedly reduced TNF-induced caspase-1 expression (transcriptional and protein levels) and IL-18 bioactivity.
    • Blocking the JAK pathway led to intracytoplasmic granular IL-18 expression, indicating impaired caspase-1 processing.

    Conclusions:

    • The JAK pathway is crucial for regulating TNF-induced IL-18 bioactivity in RA synovial fibroblasts.
    • Inhibition of caspase-1, modulated by JAK signaling, offers a novel mechanism to control IL-18 bioactivity.
    • JAK inhibition presents a promising therapeutic avenue for managing rheumatoid arthritis.

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