Regulation of inducible class II MHC, costimulatory molecules, and cytokine expression in TGF-beta1 knockout renal epithelial cells: effect of exogenous TGF-beta1.

Abstract

As reports of mice genetically deficient for TGF-β1 demonstrated aberrant renal class II MHC expression, we investigated inducible class II MHC expression on renal tubular epithelial cells derived from TGF-β1 knockout (–/–) and wild-type (+/+) mice. IFN-γ markedly upregulated class II MHC (I-Ab) expression in both (–/–) and (+/+) tubular epithelial cells. Coincubation studies of (+/+) and (–/–) tubular epithelial cells with IFN-γ+LPS, or pretreatment of these cells with TGF-β1, revealed inhibition of IFN-γ-induced I-Ab mRNA and cell surface expression that occurred via a decrease in class II transactivator gene expression in both (+/+) and (–/–) tubular epithelial cells. In addition, ICAM-1 was constitutively expressed on both (+/+) and (–/–) tubular epithelial cells and was upregulated by IFN-γ or IFN-γ+LPS. ICAM-1 expression in (+/+) and (–/–) tubular epithelial cells, however, was decreased by TGF-β1. Parallel analysis evaluating B7-1 expression detected low levels of B7-1 in unstimulated (+/+) and (–/–) tubular epithelial cells that were increased by IFN-γ, LPS, and IFN-γ+LPS. IFN-γ+LPS-mediated upregulation of B7-1 was also blocked by pretreatment with TGF-β1. Cytokine analysis detected significantly higher levels of TNF-α and MIP-1α mRNA in all treated (–/–) preparations than in (+/+) tubular epithelial cell controls. These studies demonstrate normal patterns of class II MHC, ICAM-1, and B7 expression in TGF-β1 (–/–) tubular epithelial cells in response to IFN-γ, LPS, and TGF-β1. Upregulated cytokine expression at baseline and in response to proinflammatory mediators is apparent in (–/–) tubular epithelial cells, however, and suggests that dysregulation of cytokine expression in inflammatory responses may be a primary event in multifocal inflammation observed in TGF-β1-deficient animals.