Function and survival of dendritic cells depend on endothelin-1 and endothelin receptor autocrine loops.
The biologic 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 (DCs), 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, down-regulated 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 DCs appear to be essential for the normal maturation and function of human DCs, presenting a unique target for immunomodulatory therapies.
Guruli
Georgi
G
Department of Urology, University of Pittsburgh School of Medicine, PA, USA. gurulige@umdnj.edu
Pflug
Beth R
BR
Pecher
Stefana
S
Makarenkova
Valeria
V
Shurin
Michael R
MR
Nelson
Joel B
JB
D017304:Annexin A5 / Q000494:pharmacology; D015703:Antigens, CD; D017209:Apoptosis; D016923:Cell Death; D002455:Cell Division; D002470:Cell Survival; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D015536:Down-Regulation; D019332:Endothelin-1 / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis / Q000737:chemistry; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000737:chemistry; D020411:Oligonucleotide Array Sequence Analysis; D011759:Pyrrolidines / Q000494:pharmacology; D044023:Receptor, Endothelin B / Q000378:metabolism; D017466:Receptors, Endothelin / Q000737:chemistry / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D000097802:CD83 Antigen
D017304:Annexin A5; D015703:Antigens, CD; D019332:Endothelin-1; D007136:Immunoglobulins; D018664:Interleukin-12; D008562:Membrane Glycoproteins; D011759:Pyrrolidines; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D000097802:CD83 Antigen; C120508:A 192621