Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: In forms of large vessel vasculitis (LVV) systemic IL-6 has been shown to follow disease activity. Furthermore, IL-6 inhibition is an effective treatment for giant cell arteritis, a form of LVV. Our group has demonstrated that systemic mast cell degranulation results in inhibition of LPS-induced systemic IL-6 production. Further studies demonstrated that this effect may be mediated through stimulation of histamine-1 receptor (H1R). The purpose of this study was to determine if mast cell degranulation could inhibit systemic production of IL-6 in a mouse model of vasculitis (Candida albicans water-soluble fraction induced model or CAWS).
Methods: Two month old male C57BI6/J mice were randomized to 4 groups (n=4/group). Mice were given intraperitoneal injections of either: a) normal saline (controls), b) CAWS extract, c) compound 48/80 (C48/80, systemic mast cell degranulation agent), or d) CAWS + C48/80. Injections were given on five consecutive days. Animals were sacrificed at 30 days for measurements of systemic TNF-α, INF-γ and IL-6 by ELISA as well as aortic expression of messenger RNAs coding for IL-6, suppressor of cytokine signaling-1 (SOCS1), INF-γ, IL-10 and TNF-α. Two tailed student’s T-test were used for comparisons with p<0.05 considered significant.
Results: CAWS mice had significantly higher systemic IL-6 levels compared to controls (345.2 pg/ml±132.9 vs 56.4pg/ml±19.3,p<0.001). Mice injected with C48/80 + CAWS had significantly lower IL-6 compared to CAWS alone (177.3pg/ml±113.6 vs 345.2pg/ml±132.9,p=0.02). There was significantly higher systemic INF-γ in both the CAWS and CAWS+C48/80 compared to controls. No difference in TNFα was observed between the groups. No significant differences were observed in aortic IL-6 expression between groups. Comparing CAWS+C48/80 to CAWS alone, there was significantly higher aortic expression of both SOCS1 (p<0.001) and TNF-α (p=0.03).
Conclusion: The results demonstrate that systemic mast cell degranulation inhibits systemic IL-6 levels in a mouse model of LVV. This was not accompanied by reduced aortic expression of IL-6 suggesting that this effect is occurring in other tissues, possibly the liver. Mast cell degranulation was also associated with increased aortic expression of SOCS-1, a negative inhibitor of IL-6 signaling, suggesting that mast cells may play a direct role in IL-6 signaling as well. Since our prior studies suggest mast cells mediate IL-6 production through H1R stimulation, future research will be devoted to determining if H1R inhibition can inhibit the formation of LVV in a mouse model.
Acknowledgements: Endowment from Division of Allergy, Clinical Immunology and Rheumatology and Basic Science Research Development Award from Department of Medicine, University of Kansas Medical Center
To cite this abstract in AMA style:Zhang M, Maz M, Smith D, Miura N, Ohno N, Dileepan K, Springer J. Mast Cell Mediated Inhibition of Systemic IL-6 in candida Albicans Water-Soluble Fraction (CAWS) Induced Model of Large Vessel Vasculitis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/mast-cell-mediated-inhibition-of-systemic-il-6-in-candida-albicans-water-soluble-fraction-caws-induced-model-of-large-vessel-vasculitis/. Accessed April 16, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mast-cell-mediated-inhibition-of-systemic-il-6-in-candida-albicans-water-soluble-fraction-caws-induced-model-of-large-vessel-vasculitis/