Cytokines and cellular activation in nephritis.

Introduction Macrophage infiltration related to initial glomerular damage and development of glomerulosclerosis in a Wistar–Kyoto Cytokineand chemokine-induced macrophage (Mw) and T cell activation play an important role in progress( WKY ) rat anti-GBM nephritis model ive glomerular injury in both experimental and human nephritis. Leukocyte infiltration into inflammatory Crescentic GN induced by a small dose of nephrotoxic sites requires various combinations of adhesion molecserum in WKY rats, monocyte chemotactic and activules, their ligands, and activators such as selectins, ating factor (MCAF/MCP-1), a potent Mw chemokICAM-1, and chemokines [1,2]. We investigated ine, was activated in two distinct phases; 3 days and macrophage-related chemokines and growth factors 28 days after nephrotoxic serum injection, concomitant and Th1 cell-derived cytokines which regulate the with Mw infiltration. In this model, initial administraexpression of ICAM-1 and major histocompatibility tion of polyclonal neutralizing antibodies against rat complex (MHC)-class II molecules in glomerulorecombinant MCAF/MCP-1/JE decreased the number of Mw and proliferative cellular nuclear antigen nephritis (GN). (PCNA)-positive cells in glomeruli and proteinuria both on day 3 and on day 6. Furthermore, the treatment reduced the glomerular sclerotic changes and tubulointerstitial injuries and improved renal function In situ macrophage activation recruited T cell in in the later phase of this model remarkably. However, autoimmune nephritis model, MRL-Faslpr mice delayed injection of anti-MCAF antibodies only partially improved the glomerular injuries, suggesting that Autoimmune nephritis model MRL-Faslpr mice have MCAF/MCP-1 essentially participates in the early GN, interstitial nephritis, and perivascular cell infiltstages of this experimental crescentic nephritis through rates with similarities to human lupus nephritis. In this activating as well as recruiting Mw in glomeruli [4]. model, we tested the hypothesis that cytokines attract Mw and promote renal injury in situ using the infected Adhesion molecules, chemokines and Th1 tubular epithelial cells (TEC) of the retroviral cytokine cell-derived cytokines are upregulated in genes. We used MFG recombinant retroviruses based active human GN on Moloney murine leukaemia virus encoding cDNA of murine GM-CSF or CSF-1 and injected GM-CSF or CSF-1 infected TEC into the renal subcapsular The early involvement of cellular adhesion molecules area. We detected both in vitro and in vivo CSF in human GN, glomerular P-selectin expression was production by colony forming assay and immunohistodetected in proliferative GN involving IgA nephrochemistry and found interstitial injuries with monopathy (IgAN), lupus nephritis (LN ), and acute GN (AGN ) and was correlated with endocapillary prolifnuclear cell infiltration initially composed of Mw eration and CD41b (activated platelets). Interstitial P(F4/80+ cells) followed by CD4+ T cells in autoselectin expression was also upregulated in patients immune prone mice with the Faslpr gene, suggesting with IgAN, AGN, and rapidly progressive GN both that accumulated Mw in situ recruited T cells and on the endothelial cells of peritubular capillaries and accelerated renal injury [3]. on the high-endothelial like venules associated with leukocyte infiltration. P-selectin mRNA signals detected by in situ hybridization were only observed Correspondence and offprint requests to: Hitoshi Yokoyama, Division on the capillary or venous endothelium in the interstitof Blood Purification, First Department of Internal Medicine, ium and not in the glomeruli. These observations Kanazawa University School of Medicine, 13-1 Takara-machi, Kanazawa 920-8641, Japan. suggest that P-selectin is associated with both glomer-