CHEMOKINE GENE-EXPRESSION IN ANTIGLOMERULAR BASEMENT-MEMBRANE ANTIBODY GLOMERULONEPHRITIS

Chemokines may be important in the pathogenesis of glomerular leukocyte infiltration in antiglomerular basement membrane (GEM) antibody (Ab) glomerulonephritis (GN). We studied the expression of the C-C chemokines [macrophage inflammatory protein (MIP)-1 alpha, monocyte chemotactic protein (MCP)-1, and RANTES] and C-X-C chemokines [platelet factor 4 (PF4), interferon-inducible protein of 10 kDa (IF-10), MIP-2, and cytokine-induced neutrophil chemoattractant (CINC)] at 30 min, 3, 6, 9, 15, and 24 h after induction of heterologous-phase anti-GEM Ab GN in Lewis rats. There was a rapid induction of CINC, MIP-2, MCP-1, and MIP-1 alpha mRNAs in the glomeruli of nephritic rats 30 min after administration of the anti-GEM Ab, whereas increases in PF4 and IF-10 mRNAs were not seen until 3 h. The mRNA expression of PF4, MIP-1 alpha, MIP-2, and IF-10 peaked at 3 h, whereas CINC and MCP-1 peaked at 6 and 15 h, respectively. By comparison, the expression of RANTES mRNA in rats with anti-GEM Ab GN did not differ from those of control rats. These changes in chemokine gene expression were associated with glomerular polymorphonuclear leukocytes (PMN) and monocyte/macrophage infiltration which peaked at 3 h (20.8 +/- 11.1 PMN/glomerulus) and 24 h (8.2 +/- 1.0 ED-1 cells/glomerulus), respectively. The administration of dexamethasone suppressed glomerular chemokine mRNA expression (60-98%) at both 3 and 15 h, which was associated with a 50-100% reduction in glomerular PMN and monocyte/macrophage infiltration, respectively. In vitro studies on interleukin-l-stimulated rat peritoneal macrophages demonstrated that glucocorticoids inhibited MCP-1 mRNA expression by 86%. Finally, the administration of a neutralizing Ab to CINC decreased glomerular PMN infiltration 41% (11.5 +/- 4.9 vs. 19.5 +/- 8.9 PMN/glomerulus, P = 0.006) at 3 h, which was associated with a 46% decline in glomerular myeloperoxidase content. These data provide evidence that multiple chemokines may be involved in the recruitment of leukocytes into the glomerulus in anti-GEM Ab GN.