Regulation of inducible class II MHC, costimulatory molecules, and cytokine expression in TGF-beta1 knockout renal epithelial cells: effect of exogenous TGF-beta1.
As reports of mice genetically deficient for TGF-beta1 demonstrated aberrant renal class II MHC expression, we investigated inducible class II MHC expression on renal tubular epithelial cells derived from TGF-beta1 knockout (-/-) and wild-type (+/+) mice. IFN-gamma markedly upregulated class II MHC (I-A(b)) expression in both (-/-) and (+/+) tubular epithelial cells. Coincubation studies of (+/+) and (-/-) tubular epithelial cells with IFN-gamma+LPS, or pretreatment of these cells with TGF-beta1, revealed inhibition of IFN-gamma-induced I-A(b) 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-gamma or IFN-gamma+LPS. ICAM-1 expression in (+/+) and (-/-) tubular epithelial cells, however, was decreased by TGF-beta1. Parallel analysis evaluating B7-1 expression detected low levels of B7-1 in unstimulated (+/+) and (-/-) tubular epithelial cells that were increased by IFN-gamma, LPS, and IFN-gamma+LPS. IFN-gamma+LPS-mediated upregulation of B7-1 was also blocked by pretreatment with TGF-beta1. Cytokine analysis detected significantly higher levels of TNF-alpha and MIP-1alpha 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-beta1 (-/-) tubular epithelial cells in response to IFN-gamma, LPS, and TGF-beta1. 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-beta1-deficient animals.
Banu
Nazifa
N
Renal Electrolyte and Hypertension Division, Department of Medicine, Penn Center for the Molecular Studies of Kidney Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pa, USA.
Mozes
Miklos M
MM
Kopp
Jeffrey B
JB
Ziyadeh
Fuad N
FN
Meyers
Catherine M
CM
D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018122:B7-1 Antigen; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma