G T Shin1, A Khanna, R Ding, V K Sharma, M Lagman, B Li, M Suthanthiran. 1. Department of Transplantation Medicine and Extracorporeal Therapy, The Rogosin Institute, The New York Hospital-Cornell Medical Center, New York 10021, USA.
Abstract
BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) is an immunoregulatory and fibrogenic cytokine. In an earlier in vitro study, we demonstrated that cyclosporine (CsA) increases TGF-beta1 transcription rate in human T lymphocytes. Herein, we explored whether CsA augments the in vivo expression of TGF-beta1 in humans. METHODS: The inherent difficulty in studying the in vivo effect of CsA in humans was circumvented by investigating stable end-stage renal disease patients who were preconditioned with CsA before their living donor renal transplantation. Sera and peripheral blood mononuclear cells were obtained from CsA-preconditioned patients and quantified for TGF-beta1 expression at the mRNA (by competitive polymerase chain reaction) and protein (sandwich enzyme-linked immunosorbent assay) levels. RESULTS: Our studies demonstrated a significant increase in TGF-beta1 expression after CsA therapy. The stimulatory effect was unique to TGF-beta1, and CsA did not increase interleukin (IL)-10, IL-6, IL-2, or tumor necrosis factor-alpha expression. CONCLUSIONS: Our first-time demonstration of a TGF-beta1-selective in vivo stimulatory effect of CsA in humans: (1) advances a TGF-beta1-centered hypothesis for the beneficial (immunosuppression) and detrimental (fibrosis, hypertension) effects of CsA use, and (2) broadens the mechanism of immunosuppressive action of CsA to include heightened expression of an endogenous immunosuppressive cytokine.
BACKGROUND:Transforming growth factor-beta1 (TGF-beta1) is an immunoregulatory and fibrogenic cytokine. In an earlier in vitro study, we demonstrated that cyclosporine (CsA) increases TGF-beta1 transcription rate in human T lymphocytes. Herein, we explored whether CsA augments the in vivo expression of TGF-beta1 in humans. METHODS: The inherent difficulty in studying the in vivo effect of CsA in humans was circumvented by investigating stable end-stage renal diseasepatients who were preconditioned with CsA before their living donor renal transplantation. Sera and peripheral blood mononuclear cells were obtained from CsA-preconditioned patients and quantified for TGF-beta1 expression at the mRNA (by competitive polymerase chain reaction) and protein (sandwich enzyme-linked immunosorbent assay) levels. RESULTS: Our studies demonstrated a significant increase in TGF-beta1 expression after CsA therapy. The stimulatory effect was unique to TGF-beta1, and CsA did not increase interleukin (IL)-10, IL-6, IL-2, or tumor necrosis factor-alpha expression. CONCLUSIONS: Our first-time demonstration of a TGF-beta1-selective in vivo stimulatory effect of CsA in humans: (1) advances a TGF-beta1-centered hypothesis for the beneficial (immunosuppression) and detrimental (fibrosis, hypertension) effects of CsA use, and (2) broadens the mechanism of immunosuppressive action of CsA to include heightened expression of an endogenous immunosuppressive cytokine.
Authors: Hongbo Wang; Bartosz Grzywacz; David Sukovich; Valarie McCullar; Qing Cao; Alisa B Lee; Bruce R Blazar; David N Cornfield; Jeffrey S Miller; Michael R Verneris Journal: Blood Date: 2007-05-10 Impact factor: 22.113
Authors: Julia M Barbarino; Christine E Staatz; Raman Venkataramanan; Teri E Klein; Russ B Altman Journal: Pharmacogenet Genomics Date: 2013-10 Impact factor: 2.089
Authors: Thangamani Muthukumar; John R Lee; Darshana M Dadhania; Ruchuang Ding; Vijay K Sharma; Joseph E Schwartz; Manikkam Suthanthiran Journal: Transplant Rev (Orlando) Date: 2014-05-27 Impact factor: 3.943
Authors: Kelly A Harradine; Katie Ridd; Elise F Saunier; Frederic F Clermont; Jesus Perez-Losada; Dan H Moore; Ervin H Epstein; Boris C Bastian; Rosemary J Akhurst Journal: Clin Cancer Res Date: 2009-08-11 Impact factor: 12.531
Authors: M Suthanthiran; B Li; J O Song; R Ding; V K Sharma; J E Schwartz; P August Journal: Proc Natl Acad Sci U S A Date: 2000-03-28 Impact factor: 11.205