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Short-term hyperthermia prevents activation of proinflammatory genes in fibroblast-like synoviocytes by blocking the activation of the transcription factor NF-κB

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Abstract

Fibroblast-like synoviocytes (FLS) play a key role in the genesis of rheumatoid arthritis (RA). FLS are among the most versatile cells with the potential to activate an array of genes that are able to initiate and propagate inflammation in RA-affected joints. Controlling activation of FLS might hold the key to restraining inflammation in RA-affected joints. In this study, we investigate the effect and mechanisms of short-term hyperthermia on a series of proinflammatory genes in FLS. In vitro experiments demonstrate that exposure of FLS to elevated temperatures for the duration of 30 min prevents activation of a series of genes with proinflammatory properties. Exposure to hyperthermia reduces IL-1β-induced prostaglandin E2 release, suppresses activation of the adhesion molecules VCAM-1, ICAM-1, the cytokines TNFα, IL-1α, IL-1β, IL-8 as well as COX-2 protein synthesis. Real time reverse transcriptase-polymerase chain reaction showed that hyperthermia altered gene expression at the transcriptional level. The amount and the duration of inhibition is gene-specific and lasts for up to 25 h. As to the mechanism of inhibition, electrophoretic mobility shift assay experiments demonstrated that exposure of FLS to hyperthermia prevents IL-1β-induced NF-κB translocation and subsequent DNA binding. Many mechanisms have been shown to be involved in hyperthermia-mediated effects on NF-κB-DNA interactions. We demonstrate by Western blot experiments that in FLS, hyperthermia prevents the phosphorylation and subsequent degradation of IκBα, therefore retaining the NF-κB complex in the cytoplasm. Carefully controlled in vivo tests are certainly needed before one can take full advantage of those phenomena; however, the ease by which the temperature in joints can be modulated might offer an opportunity for manipulating inflammatory processes in joints by simple balneological means.

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Acknowledgements

This work was supported in part by grants from the City of Vienna, the Austrian Ministry of Health and Women (236065/008-I/A/Ib/2004), the Austrian Ministry of Education, Science and Culture, and the “Medizinisch-Wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien”. MM is supported by a fellowship of the IFCC. This manuscript is part of the thesis work requirements of MM carried out at the LBI for Rheumatology and Balneology under the supervision of KMS.

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  1. Institute of Medical Biochemistry, Clinical Center of Serbia, Belgrade, Serbia

    Marica Markovic

  2. Ludwig Boltzmann Institute for Rheumatology and Balneology, Kurbadstrasse 10, 1100, Vienna, Austria

    Marica Markovic & Karl M. Stuhlmeier

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  1. Marica Markovic
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Correspondence to Karl M. Stuhlmeier.

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Markovic, M., Stuhlmeier, K.M. Short-term hyperthermia prevents activation of proinflammatory genes in fibroblast-like synoviocytes by blocking the activation of the transcription factor NF-κB. J Mol Med 84, 821–832 (2006). https://doi.org/10.1007/s00109-006-0089-6

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