Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Endothelial Anti-Inflammatory Effect of alpha2 Adrenergic Agonists.
Herrera2, Ada, Dominguez2, M. Jesús, Arce2, M. Teresa, Diaz2, A., Feria1, Manuel, Diaz2, Federico
Our group has observed that a2 adrenergic agonists are able to modulate the inflammatory response in animal models of inflammation. However, the mechanisms thought which a2 adrenergic receptors participate in the regulation of the inflammatory response have not been clarified.
To study the mechanisms responsible for the antiinflammatory action of a2 agonists.
Surface expression of L-selectin, CD11b, ICAM-1 and VCAM-1 were assessed by flow cytometry. The a2 agonists, xylazine and UK14304, and the a2 antagonist, RX821002 were used in this work. The presence of the a2 adrenergic receptor subunits: A, B and C were investigated by RT-PCT and Western blot. Neutrophil migration capability through activated endothelium was assessed in transwell assay (5mm). The dynamic interaction between neutrophils and activated endothelium was studied in a flow chamber. The endothelial intercellular junction was analyzed by the cell distribution of VE-Cadherin and CD31 by confocal microscopy. Wilcoxon signed-rank test (p<0.05) was used to evaluate the statistical significance.
Both neutrophils and HUVEC expressed mRNA transcripts of the three subunits of a2 adrenergic receptor. However, only the presence of receptors a2A, in PMN and a2B, in HUVEC were detected by western blot. Basal expression of L-selectin and CD11b, in neutrophils and VCAM-1, in HUVEC were not modified by the presence of a2 agonists. However, ICAM-1 basal expression in TNF-a-activated HUVEC showed a significative dose-dependent reduction in the presence of UK 14304. When HUVEC where activated in the presence of UK14304, the basal migration of human neutrophils through activated HUVEC in static conditions was decreased up to 40±8%. This effect was reverted by RX821002. When neutrophils were incubated with UK14304 no effect on cell migration was observed. The presence of the agonist a2 UK 14,304 did not interfere with the ability of PMN rolling on activated vascular endothelium, but it reduced the transmigration ability of neutrophils by 60% under shear stress conditions. The endothelial intercellular surface positive for VE-Cadherin and CD31 staining was increased in a 50% by UK14.308 respect to the basal.
The a2 adrenergic agonists are able to modulate the inflammatory response at endothelium level. These compounds seem to increase the endothelial cell-cell interaction resulting in a reduction of the neutrophil movement across the endothelial barrier. This finding supports the endothelium as a therapeutic target for developing new anti-inflammatory agents potentially useful for inflammatory rheumatic diseases.
To cite this abstract, please use the following information:
Herrera, Ada, Dominguez, M. Jesús, Arce, M. Teresa, Diaz, A., Feria, Manuel, Diaz, Federico; Endothelial Anti-Inflammatory Effect of alpha2 Adrenergic Agonists. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1659