Background/Purpose: IL-6 plays an important role in the pathogenesis of large vessel vasculitis.  Lipopolysaccharide (LPS), acting through toll-like receptor 4, enhances both the aortic expression as well as serum levels of IL-6.  Previous work by our group has demonstrated that systemic mast cell degranulation will inhibit both the serum and aortic expression of IL-6 in LPS injected mice.  Mast cells release many vasoactive substances including histamine, proteases, and IL-10 .  Our hypothesis is that the inhibitory effect of mast cells on aortic IL-6 production is mediated through histamine and/or IL-10.

Methods: Two month-old male C57BI6 (WT) and Histamine 1 Receptor (H1R) -/- mice were randomized into four groups, and given intraperitoneal injections with normal saline (control),  compound 48/80 (mast cell degranulation agent, 1mg/kg), LPS (1mg/kg) or C48/80+LPS.  Mice were sacrificed 24-h later, and levels of the stable metabolites of prostaglandin I₂ (PGI₂) and thromboxane A₂ (TXA₂) in the urine, and IL-6 and IL-10 in sera were quantified.

Results: MC degranulation did not increase PGI₂ in control or in LPS-treated mice of either genotype. LPS injection increased PGI₂ in both genotypes, but the increase was higher in H1R-/- mice. Both C48/80 and LPS increased TXA₂ in WT mice, but only LPS treatment enhanced TXA₂ in H1R-/-mice indicating importance H1R in this pathway.  Treatment with C48/80 did not further enhance prostanoid production over LPS.  LPS treatment increased serum IL-6 in both genotypes, but the changes were significant only in WT mice.  Interestingly, LPS-induced IL-6 production was significantly reduced by MC degranulation in WT mice, but not in H1R-/- mice.  In WT mice the inhibition of IL-6 was associated with enhanced aortic expression of SOCS1.  In comparison to WT, the basal and induced levels of IL-10 were markedly higher in H1R-/- mice. 

Conclusion: Mast cells differentially regulate LPS-induced inflammatory response in WT and H1R -/- mice.  These results suggest that MCs regulate LPS-induced systemic and aortic inflammatory response involving H1R, SOCS-1 and IL-10.

Acknowledgements: Supported by NIH grants R01-HL070101 & 3R01-HL070101-04S1, the Joseph & Elizabeth Carey Arthritis Fund and Audrey Smith Fund from KU Endowment Association, Lied Grant from KUMC Research Institute, and by the Department of Internal Medicine Research Office. H1R-null breeding pairs were graciously provided by Dr. Cory Teuscher, University of Vermont, Burlington, VT.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/mast-cell-regulation-of-aortic-il-6-expression-involves-histamine-1-receptor-suppressor-of-cyotkine-signaling-1-and-il-10/