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TGF-beta1 down-regulates induced expression of both class II MHC and B7-1 on primary murine renal tubular epithelial
1University of Pennsylvania School of Medicine, Penn Center for the Molecular Studies of Kidney Diseases, Department of Medicine, Philadelphia 19104, USA.
Background:
We examined the immunomodulatory effects of transforming growth factor-beta1 (TGF-beta1) on the regulation of class II MHC and costimulatory molecule expression in a primary renal tubular epithelial cell line, called F1K.
Methods:
Class II major histocompatibility complex (MHC), class II transactivator, B7-1, intercellular adhesion molecule-1 (ICAM-1) and interferon-gamma (IFN-gamma) receptor beta chain were evaluated in untreated and cytokine-treated F1K by Northern hybridization analysis and flow cytometry. T cell activation studies were performed to assess TGF-beta1-mediated effects on antigen presenting cell function of F1K.
Results:
Pretreatment of F1K with TGF-beta1 markedly inhibited IFN-gamma-induced class II MHC expression, by both FACS and Northern analysis. Total class II transactivator mRNA levels were also diminished by TGF-beta1, indicating that class II MHC modulation in F1K results from inhibition of this intermediate protein. As previous studies demonstrated that cotreatment of F1K cells with IFN-gamma + lipopolysaccharide (LPS) induces B7-1, we evaluated the potential regulatory effects of TGF-beta1 exposure on B7-1 expression. Our studies revealed that B7-1 mRNA and cell-surface expression in IFN-gamma + LPS-treated F1K were decreased by TGF-beta1 pretreatment. Functional studies evaluating TGF-beta1-mediated effects were performed with IFN-gamma + LPS-treated F1K and MR1.3, a nephritogenic CD4+ Th2 clone derived from kidneys of animals with autoimmune glomerulonephritis. Interleukin (IL)-4 production assays demonstrated activation of MR1. 3 by IFN-gamma + LPS-treated cells, but not by IFN-gamma + LPS-treated cells previously exposed to TGF-beta1, indicating that TGF-beta1-mediated inhibition of class II MHC and B7-1 expression alters the antigen presenting cell function of F1K.
Conclusions:
These studies describe the proscriptive influence of TGF-beta1 on class II MHC and B7-1 expression in renal tubular epithelial cells. Such findings indicate that TGF-beta1 alters the antigen presenting cell function of renal tubular epithelial cells in vitro, and suggest a potential mechanism for immunosuppression of T cell-mediated renal immune responses in vivo.