Activation of pro-inflammatory and anti-inflammatory cytokines in host organs during chronic allograft rejection: role of endothelin receptor signaling.
This study investigated whether allograft rejection is associated with local inflammatory activation in host organs and whether endothelin ET(A) receptor signaling is involved. Expression of IL-1beta, IL-1ra, IL-6, IL-10 and TNF-alpha was investigated in host liver, lung and native heart in a rat model of chronic rejection 8 weeks after heterotopic cardiac transplantation in the absence of immunosuppression. In the presence of rejection, circulating levels of cytokines increased, while tissue level activation was dependent on the organ involved. Similarly, tissue-specific regulatory patterns were observed regarding transcriptional activation. Although chronic ET(A) receptor blockade did not reduce transplant vasculopathy or tissue protein expression, treatment had pronounced effects on plasma levels and transcriptional regulation of chemokines. These data provide evidence for distinct pro-inflammatory local activation in host organs during chronic rejection and suggest a role for ET(A) receptors contributing to regulation of cytokine plasma levels and transcriptional activity.
Lattmann
Thomas
T
Medical Policlinic, Department of Medicine, University Hospital, Zürich, Switzerland.
Hein
Marc
M
Horber
Sibylle
S
Ortmann
Jana
J
Teixeira
Mauro M
MM
Souza
Danielle G
DG
Haas
Elvira
E
Tornillo
Luigi
L
Münter
Klaus
K
Vetter
Wilhelm
W
Barton
Matthias
M
D000818:Animals; D001161:Arteriosclerosis; D003331:Coronary Vessels / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D006084:Graft Rejection; D016027:Heart Transplantation; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009206:Myocardium / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D044022:Receptor, Endothelin A / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000096:biosynthesis; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C107831:darusentan; D012313:RNA