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 Blood, 1 October 2004, Vol. 104, No. 7, pp. 2107-2115.
Prepublished online as a Blood First Edition Paper on June 22, 2004; DOI 10.1182/blood-2003-10-3559.

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Submitted October 20, 2003
Accepted May 7, 2004

Dendritic cells function and survival are dependent on endothelin-1 and endothelin receptors autocrine loops

Georgi Guruli*, Beth R Pflug, Stefana Pecher, Valeria Makarenkova, Michael R Shurin, and Joel B Nelson

Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

* Corresponding author; email: gurulige{at}umdnj.edu.

The biological effects of endothelin-1 (ET-1) are not limited to its potent vasoconstricting activity. The endothelin receptors, ETA and ETB, have differential tissue and functional distributions. Here we showed that dendritic cells (DC), the major antigen-presenting cells in the adaptive limb of the immune system, produce large amounts of ET-1 and significantly increase the expression of endothelin receptors upon maturation. Selective blockade of the ETA receptor significantly reduced expression of the mature DC marker CD83, decreased the production of the immunostimulatory cytokine interleukin-12, downregulated DC ability to stimulate T cells, and promoted DC apoptosis. Selective ETB receptor blockade, on the other hand, resulted in increased expression of CD83 and improved DC survival. Therefore, ET-1/ETA/ETB autocrine/paracrine loops on DC appear to be essential for the normal maturation and function of human DC, presenting a unique target for immunomodulatory therapies.


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