INTRARENAL CYTOKINE MESSENGER-RNA EXPRESSION AND LOCATION IN NORMAL AND IGA NEPHROPATHY TISSUE - TGF-ALPHA, TGF-BETA, IGF1, IL-4 AND IL-6

Peptide regulatory factors (PRFs) are critical components in the regulation of glomerular inflammatory response to immune injury and may also have a primary role in modulating intrinsic cell proliferation and matrix synthesis. Dysregulation of PRFs and glomerular infiltration with inflammatory, including mononuclear, cells occur in models of nephritis, but direct evidence for their role is not established in normal and diseased tissue in man. Using in situ hybridization techniques capable of detecting specific cellular messenger RNA we have evaluated normal human and IgA nephropathy diseased renal tissue for expression and location of PRF encoding mRNA. Permeabilized tissue was examined by autoradiography using S-35 labelled-antisense, and -sense riboprobes for TGF alpha, TGF beta, IGF 1, IL-4, and IL-6 encoding mRNA. TGF beta was constitutively expressed in normal glomerular mesangium, capillary loop, Bowman's capsule, and vascular endothelial and tubular cells, but was downregulated in IgA nephropathy tissue. In contrasting and distinct patterns, TGF alpha encoding mRNA was found in neither tissue, whereas IGF 1 mRNA was expressed in normal and also in diseased tissue. IGF 1 mRNA activity was intense within tubular cell cytoplasm in normals, with similar characteristics in IgA nephropathy. Cytokines IL-4 and IL-6 mRNAs were absent in normals, with IL-4 detectable throughout renal substance in disease; IL-6 gene transcription was intense in glomerular and vascular endothelial sites in IgA nephropathy. These findings implicate selective gene induction and suppression in disease, suggesting functional downregulation of glomerular TGF beta, coincident with autocrine functions for IL-6 and IL-4 in the pathogenesis of IgA-related nephropathy.