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

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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/