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Activation of histamine H4 receptor inhibits TNFα/IMD-0354-induced apoptosis in human salivary NS-SV-AC cells

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Abstract

Apoptosis is involved in the pathogenesis of Sjögren’s syndrome (SS), an autoimmune disease affecting exocrine glands. Our recent studies revealed diminished histamine H4 receptor (H4R) expression and impaired histamine transport in the salivary gland epithelial cells in SS. The aim was now to test if nanomolar histamine and high-affinity H4R signaling affect apoptosis of human salivary gland epithelial cell. Simian virus 40-immortalized acinar NS-SV-AC cells were cultured in serum-free keratinocyte medium ± histamine H4R agonist HST-10. Expression and internalization of H4R were studied by immunofluorescence staining ± clathrin inhibitor methyl-β-cyclodextrin (MβCD). Apoptosis induced using tumor necrosis factor-α with nuclear factor-κB inhibitor IMD-0354 was studied using phase contrast microscopy, Western blot, flow cytometry and polymerase chain reaction (qRT-PCR). HST-10-stimulated H4R internalization was inhibited by MβCD. Western blotting revealed diminished phosphorylated c-Jun N-terminal kinase JNK, but unchanged levels of phosphorylated extracellular signal regulated kinase pERK1/2 in H4R-stimulated samples compared to controls. qRT-PCR showed up-regulated expression of anti-apoptotic B cell lymphoma-extra large/Bcl-xL mRNAs and proteins, whereas pro-apoptotic Bcl-2-associated X protein/BAX remained unchanged in H4R-stimulated samples. H4R stimulation diminished cleavage of PARP and flow cytometry showed significant dose-dependent inhibitory effect of H4R stimulation on apoptosis. As far as we know this is the first study showing inhibitory effect of H4R activation on apoptosis of human salivary gland cells. Diminished H4R-mediated activation may contribute to loss of immune tolerance in autoimmune diseases and in SS in particular.

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Acknowledgments

We acknowledge all participating centers and members of the TULES-research group who actively supported this study. We also acknowledge our funding sources: Orion Farmos, MedCare-säätiö, Finska Läkaresälskapet, Maire Lisko Säätiö, Suomen Reumatologinen Yhdistys.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

    Vasili Stegajev, Vesa-Petteri Kouri, Abdelhakim Salem, Dan C. E. Nordström & Yrjö T. Konttinen

  2. Department of Anatomy, University of Helsinki, Helsinki, Finland

    Vasili Stegajev, Vesa-Petteri Kouri, Abdelhakim Salem & Stanislav Rozov

  3. Institut fuer Pharmazeutische and Medizinische Chemie, Heinrich-Heine-Universitaet Duesseldorf, Duesseldorf, Germany

    Holger Stark

  4. ORTON Orthopaedic Hospital of the ORTON Foundation, Helsinki, Finland

    Yrjö T. Konttinen

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  1. Vasili Stegajev
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Correspondence to Yrjö T. Konttinen.

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Stegajev, V., Kouri, VP., Salem, A. et al. Activation of histamine H4 receptor inhibits TNFα/IMD-0354-induced apoptosis in human salivary NS-SV-AC cells. Apoptosis 19, 1702–1711 (2014). https://doi.org/10.1007/s10495-014-1036-6

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