Clinical Investigation

Kidney International (1992) 42, 95–101; doi:10.1038/ki.1992.266

IL-1 receptor antagonist inhibits monocyte chemotactic peptide 1 generation by human mesangial cells

Zarin Brown, Robert M Strieter, Guy H Neild, Robert C Thompson, Steven L Kunkel and John Westwick

Department of Pharmacology, University of Bath, Avon, England, United Kingdom; Departments of Internal Medicine and Pathology, University of Michigan, Ann Arbor, Michigan, USA; Department of Renal Medicine, Institute of Urology and Nephrology, University College London, United Kingdom; Synergen, Inc., Boulder, Colorado, USA

Correspondence: Dr Z Brown, Dept. of Pharmacology, University of Bath, Claverton Down, Avon, England, BA2 7AY, United Kingdom.

Received 2 December 1991; Accepted 30 January 1992.

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Abstract

IL-1 receptor antagonist inhibits monocyte chemotactic peptide 1 generation by human mesangial cells. The elicitation of neutrophils and monocytes from the circulation into the inflamed glomerulus is a key process in the pathogenesis of proliferative glomerulonephritis. The aim of this study was to determine the factors which regulate the expression and synthesis of the monocyte specific chemotaxin, monocyte chemotactic peptide 1 (MCP-1). Mesangial cells in culture did not constitutively express MCP-1, but could be induced to express both MCP-1 mRNA and antigenic MCP-1 by either stimulation with IL-1alpha or TNFalpha, which are also stimuli for interleukin 8 (IL-8/NAP-1) expression and release. Pre-treatment of mesangial cells with the IL-1 receptor antagonist (IL-1ra) induced dose-dependent inhibition of both the expression of MCP-1 and IL-8 mRNA as well as the release of both chemotactic peptides in response to IL-1alpha, while the receptor antagonist had no significant effect on TNFalpha induced MCP-1 and IL-8 generation. This study demonstrates that the IL-1 receptor antagonist was four times more effective at inhibiting the IL-1 induced expression and release of IL-8 compared to that of MCP-1. These results suggest that mesangial cell-derived MCP-1 may play an important role in the recruitment of monocytes in glomerular inflammation and that an IL-1 receptor antagonist may have therapeutic potential for the treatment of glomerulonephritis.

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