title: Activation of pro-inflammatory and anti-inflammatory cytokines in host organs during chronic allograft rejection: role of endothelin receptor signaling.
abstract: 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.
authors.affiliation: Medical Policlinic, Department of Medicine, University Hospital, Zürich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lattmann
authors.forename: Marc
authors.initials: M
authors.lastname: Hein
authors.forename: Sibylle
authors.initials: S
authors.lastname: Horber
authors.forename: Jana
authors.initials: J
authors.lastname: Ortmann
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Danielle G
authors.initials: DG
authors.lastname: Souza
authors.forename: Elvira
authors.initials: E
authors.lastname: Haas
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
authors.forename: Klaus
authors.initials: K
authors.lastname: Münter
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Vetter
authors.forename: Matthias
authors.initials: M
authors.lastname: Barton
mesh_terms: 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
chemical_list: 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