The Heat Shock Protein 90 (HSP90) Is Required for the IL-33-Induced Cytokine Production in Mast Cells (MCs)

GND
1285288416
ORCID
0000-0001-8473-2337
Zugehörigkeit
Institut of Immunology, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Leutragraben 3, 07743 Jena, Germany
Peters, Isabel;
GND
12936231X
Zugehörigkeit
Institut of Immunology, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Leutragraben 3, 07743 Jena, Germany
Müller, Sylvia;
GND
1285319761
Zugehörigkeit
Institut of Immunology, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Leutragraben 3, 07743 Jena, Germany
Küchler, Claudia;
GND
1285320352
Zugehörigkeit
Institut of Immunology, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Leutragraben 3, 07743 Jena, Germany
Jäger, Ute;
GND
131652532
Zugehörigkeit
Institut of Immunology, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Leutragraben 3, 07743 Jena, Germany
Drube, Sebastian

The alarmin interleukin-33 (IL-33) is released upon cell stress and damage in peripheral tissues. The receptor for IL-33 is the Toll/Interleukin-1 receptor (TIR)-family member T1/ST2 (the IL-33R), which is highly and constitutively expressed on MCs. The sensing of IL-33 by MCs induces the MyD88−TAK1−IKK2-dependent activation of p65/RelA and MAP-kinases, which mediate the production of pro-inflammatory cytokines and amplify FcεRI-mediated MC-effector functions and the resulting allergic reactions. Therefore, the investigation of IL-33-induced signaling is of interest for developing therapeutic interventions effective against allergic reactions. Importantly, beside the release of IL-33, heat shock proteins (HSPs) are upregulated during allergic reactions. This maintains the biological functions of signaling molecules and/or cytokines but unfortunately also strengthens the severity of inflammatory reactions. Here, we demonstrate that HSP90 does not support the IL-33-induced and MyD88−TAK1−IKK2-dependent activation of p65/RelA and of mitogen-activated protein (MAP)-kinases. We found that HSP90 acts downstream of these signaling pathways, mediates the stability of produced cytokine mRNAs, and therefore facilitates the resulting cytokine production. These data show that IL-33 enables MCs to perform an effective cytokine production by the upregulation of HSP90. Consequently, HSP90 might be an attractive therapeutic target for blocking IL-33-mediated inflammatory reactions.

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