Chemokine gene expression in anti-glomerular basement membrane
antibody glomerulonephritis.
Tang, Winson W., Songmei Yin, Arthur J. Wittwer, Meiying Qi.
Department of Anatomic Pathology, Amgen Inc., Thousand Oaks, CA
91320 and Monsanto Corporate Research, Monsanto Company, St Louis, MO
63167
APStracts 2:0071F, 1995.
Chemokines may be important in the pathogenesis of glomerular
leukocyte infiltration in anti-GBM Ab GN. We studied the expression
of the C-C (MIP-1a, MCP-1, and RANTES) and C-X-C (PF4, IP-10, MIP-2
and CINC) chemokines 30 minutes, 3, 6, 9, 15 and 24 hrs after
induction of heterologous phase anti-GBM Ab GN in Lewis rats. There
was a rapid induction of CINC, MIP-2, MCP-1 and MIP-1a mRNAs in the
glomeruli of nephritic rats 30 minutes after administration of the
anti-GBM Ab, while increases in PF4 and IP-10 mRNAs were not seen
until 3 hrs. The mRNA expression of PF4, MIP-1a, MIP-2 and IP-10
peaked at 3 hrs while CINC and MCP-1 peaked at 6 and 15 hrs,
respectively. By comparison, the expression of RANTES mRNA in rats
with anti-GBM Ab GN did not differ from those of control rats. These
changes in chemokine gene expression were asociated with glomerular
PMN and monocyte/macrophage infiltration which peaked at 3 (20.8+11.1
PMN/glom) and 24 (8.2+1.0 ED-1 cells/glom) hrs, respectively. The
administration of dexamethasone suppressed glomerular chemokine mRNA
expression (60-98%) at both 3 and 15 hrs which was associated with a
50-100% reduction in glomerular PMN and monocyte/macrophage
infiltration, respectively. In vitro studies on IL-1 stimulated rat
peritoneal macrophages demonstrated that glucocorticoids inhibited
MCP-1 mRNA expression 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/glom, P=0.006) at 3 hrs 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-GBM Ab
GN.
Received 9 November 1994; accepted in final form 8 March 1995.
APS Manuscript Number F401-4.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 2 May 1995.