Background/Purpose
Early in the pathogenesis of Giant Cell Arteritis (GCA) dendritic cells interact with T cells of both Th1 and Th17 origin. IL-6; released by Th17 T-cells, macrophages and endothelial cells; plays an important role in the pathogenesis of GCA. Mast cells (MCs) are important constituents of the immune system. They possess both pro-inflammatory and anti-inflammatory functions. There is an increased presence of mast cells in the temporal arteries of GCA patients. Furthermore, MCs have been shown to have an immunomodulatory effect in an MPO-associated vasculitis mouse model. The mechanism by which MCs modulate vascular inflammation in large vessel vasculitis, such as GCA, is not known. Suppressor of Cytokine Signaling-1 (SOCS-1), a JAK-STAT inhibitor, plays a role in inhibiting cytokine signaling. The objective of this study was to test the hypothesis that MCs regulate LPS induced aortic IL-6 production through SOCS-1 proteins.
Methods
Two month old male C57Bl/6J mice were randomized into 4 treatment groups. The treatment groups were administered intraperitoneal injections with: saline (control), Compound 48/80 (C48/80, MC degranulating agent, 1mg/kg), LPS (1mg/kg) or C48/80+LPS. Mice were sacrificed at either 24 hours (single injection) or 10 days (serial injections), and blood and aortas were collected for various analyses as presented in ‘Results ’. Data were analyzed for statistical significance and p < 0.05 was considered significant.
Results
In the single injection groups, LPS significantly enhanced serum IL-6 (350±146 pg/ml vs 21.3±5.5 pg/ml) and aortic IL-6 gene expression (18.0±5.4 fold vs 1.03±0.025 fold) compared to normal saline-injected mice. When MCs were degranulated by C48/80, LPS-induced aortic expression of IL-6 and serum IL-6 were significantly reduced when compared to LPS alone (IL-6: 101±13 pg/ml vs 350±146 pg/ml; IL-6 mRNA: 4.3±0.5 vs 18.0±5.4 fold change). Aortic expression of SOCS-1 mRNA was found to be 2- and 3- fold higher, respectively, in the LPS and C48/80 + LPS groups compared to controls. In mice receiving serial injections, there were significantly higher levels of IL-18 and tissue inhibitor of metalloproteinase-1 (p<0.0001) in the LPS and LPS+C48/80 groups compared to controls. Thrombopoetin was significantly higher in the LPS group compared to the C48/80 and control groups but no difference was seen between C48/80 + LPS compared to C48/80 group alone. No significant differences between groups were seen for IL-1 alpha, IL-1 beta, monocyte chemotactic protein (MCP) 1, MCP-3 or VEGF-A.
Conclusion
These results demonstrate that MC degranulation inhibits LPS- induced aortic expression of IL-6 and systemic production of IL-6. The inhibitory effect of MCs was associated with an increased expression of SOCS-1 in the aorta. This suggests that SOCS-1 plays a role in mast cell-mediated regulation of IL-6 as well as other cytokines associated with the pathogenesis of GCA homeostasis. Identifying the MC factor or factors involved in the inhibition of LPS-induced inflammation in the aorta may provide novel therapeutic strategies for GCA.
Disclosure:
J. Springer,
None;
V. Raveendran,
None;
D. Smith,
None;
M. Maz,
None;
K. Dileepan,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-inhibitory-effects-of-mast-cells-in-aortitis-involves-aortic-expression-of-suppressor-of-cytokine-signaling-1/