Article
Intraadrenal Dendritic Cells and Macrophages Inhibit Corticosterone Response during Collagen-induced Arthritis – a Role for IL-1β and CXC chemokines?
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Authors
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Hubert Stangl
- University Hospital Regensburg, Lab. of Exp. Rheumatology & Neuroendocrine Immunology, Regensburg
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Christine Wolff
- University Hospital Regensburg, Lab. of Exp. Rheumatology & Neuroendocrine Immunology, Regensburg
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Martin Lesiak
- University Hospital Regensburg, Lab. of Exp. Rheumatology & Neuroendocrine Immunology, Regensburg
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Anita Krammetsvogl
- University Hospital Regensburg, Lab. of Exp. Rheumatology & Neuroendocrine Immunology, Regensburg
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Angelika Gräber
- University Hospital Regensburg, Lab. of Exp. Rheumatology & Neuroendocrine Immunology, Regensburg
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Rainer H. Straub
- University Hospital Regensburg, Lab. of Exp. Rheumatology & Neuroendocrine Immunology, Regensburg
| Published: | September 4, 2017 |
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Outline
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Background: In rheumatoid arthritis (RA) and collagen-induced arthritis (CIA) the phenomenon of relative insufficiency of adrenal glands to produce an adequate amount of glucocorticoids in later stages of the disease is well known (Spiess et al., Wolff et al.). Additionally, the presence and migration of macrophages and dendritic cells (DCs) in and into the pituitary and adrenal gland has been described (Glennon et al., Sato, Engstrom et al.). We hypothesized that these cells contribute to the inadequate glucocorticoid secretion during RA.
Methods: CIA was induced in DA-rats. Cytokines in supernatants from whole adrenal gland cells, adrenal gland cells after magnetic bead separation for macrophage/DC markers MHCII and CD11b, and from bone marrow-derived DCs (BMDC) were quantified with ELISA. The corticosterone secretion from whole adrenal gland cells in co-culture with BMDCs was quantified with ELISA.
Results: Analysis of supernatants revealed a similar profile of the C-X-C ligand chemokines CINC-1,-2,-3 (Cytokine-induced neutrophil chemoattractant), LIX (LPS-induced CXC chemokine) and of the cytokine IL-1β in supernatants from BMDCs and whole adrenal gland cells. BMDCs generated from arthritic rats expressed significantly more IL-1β, CINC-1,-2,-3, and LIX (all p<0.001) compared to controls. Levels of IL-1β (p<0.001) and CINC-2 (p=0.034) in supernatants from arthritic whole adrenal gland cells were significantly higher compared to controls. Co-culture experiments revealed an inhibitory effect of BMDCs from control and arthritic rats on the corticosterone response of whole adrenal gland cells (p<0.001).
Stimulation of whole adrenal gland cells and of BMDCs with IL-1β increased protein expression of CINC-1,-2,-3 and LIX, and was dose dependently blocked by the IL-1 receptor antagonist. Here, both, adrenal gland cells and BMDCs derived from arthritic animals showed higher baseline expression and higher expression after stimulation with IL-1β compared to cells derived from control animals (p<0.001).
Further, magnetic bead cell separation indicated that MHCII+ rather than CD11b+ adrenal gland cells are the main source of intraadrenal chemokines.
Conclusion: DCs and macrophages are present in adrenal glands and inhibit corticosterone production, possibly via IL-1β, CINC-1,-2,-3 and LIX. Specific targeting of these cells, IL-1β, and IL-1β-driven upregulation of chemokines might prevent relative adrenal gland insufficiency during arthritis and, hence, could be a future therapy.
