Artikel
Bregs are regulated by a catecholamine-driven autocrine mechanism
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Autoren
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Nadine Honke
- Poliklinik und Funktionsbereich für Rheumatologie, Hiller Forschungszentrum Rheumatologie, Medizinische Fakultät, Heinrich-Heine Universität, Düsseldorf
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Birgit Opgenoorth
- Poliklinik und Funktionsbereich für Rheumatologie & Hiller Forschungszentrum Rheumatologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Rheumatologie, Düsseldorf
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Katharina Krebber
- Medizinische Fakultät, Heinrich-Heine Universität, Rheumatologie, Poliklinik, Funktionsbereich & Hiller Forschungszentrum, Düsseldorf
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Torsten Lowin
- Poliklinik, Funktionsbereich & Hiller Forschungszentrum für Rheumatologie, UKD, Heinrich-Heine-Universität Düsseldorf, Düsseldorf
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Matthias Schneider
- Poliklinik, Funktionsbereich & Hiller Forschungszentrum für Rheumatologie, UKD, Heinrich-Heine-Universität Düsseldorf, Düsseldorf
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Georg Pongratz
- Universitätsklinikum Düsseldorf, Poliklinik, Funktionsbereich & Hiller Forschungszentrum für Rheumatologie, Düsseldorf
| Veröffentlicht: | 8. Oktober 2019 |
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Gliederung
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Background: It has been shown that release of catecholamines by the SNS modulates development and course of RA. In the current study, we investigated whether regulatory B cells have ADRs and their own machinery for catecholamines production to determine if autocrine mechanisms could contribute to controlling regulatory B cell function.
Methods: On IgM/CpG-activated murine B cells, the basics for the mechanism(s) of increased regulatory B cell function and its targeted influence were investigated. TH as well as the expression of ADRs were analyzed in naïve (0h) or IgM/CpG activated B cells by FACS, Western Blot and qRT-PCR. For analysis of IL-10 production released IL-10 from inactivated and activated B cells were quantified in supernatant of B cell cultures by ELISA or directly in B cells by intracellular FACS staining.
Results: TH is strongly expressed by B cells after activation. Analysis of B cells by FACS showed a raised expression of TH with duration of activation (0h vs. 24h, n=7-12, p***<0,0001; 0h vs. 48h, n=7-12, p***<0,0001; 24h vs. 48h, n = 12, p**=0,0091). A sign that catecholamines are not only provided by the sympathetic nervous system, but also produced by B cells. Furthermore, qRT-PCR and FACS showed that all adrenergic receptors (ADR) determined (ADRα1a, ADRα1b, ADRα2b, ADRß1 and ADRβ2) are expressed on the surface of IgM/CpG-activated B cells (n=12). The number of TH+ cells, as ascertained by FACS correlates with the expression of ADRα1a (r=0.575, p=0.2, n=6), ADRα2b (r=0.582, p=0.046, n=12), and ADRβ2 (r=0.742, p=0.006, n=12) After activation with IgM/CpG B cells produce IL-10 as determined by ELISA (n=6, p***<0,0001) and FACS (n=5, p***<0,0001) and the production can be increased by addition of isoproterenol, a ADRbeta agonist (n=12, p**=0,006), an effect that was blocked by nadolol (n=12, p*=0,0293). FACS analysis showed that IL-10 was mainly produced by TH+ B cells (n=6, p***<0,0001).
Conclusion: In conclusion, our data suggest that IgM/CpG-induced expression of TH in murine B cells is associated with an increase in IL-10 mediated by stimulation of beta ADRs. This might point to an autocrine mechanism to control regulatory B cells, which could be exploited for therapeutic purposes in RA.
Abbreviations: Bregs: regulatory B cells, SNS: sympathetic nervous system, TH: tyrosine hydroxylase
