The in Vitro Immunomodulatory Effects of Sulfasalazine on Human Polymorphonuclear Leukocytes, Mononuclear Cells, and Cultured Glomerular Mesangial Cells

Sulfasalazine (SSA) was investigated for its effects on phagocytic activity of normal human polymorphonuclear neutrophils (PMN), proliferation of mononuclear cells (MNC) and cultured glomerular mesangiai cells. At concentrations from 25 to 100 mu M, it inhibited phagocytic activity of PMN and the H-3-thymidine incorporation of phytohemagglutinin ( PHA)-stimulated human MNC in a dose-dependent manner. At comparable concentrations, sulfapyridine and 5- aminosalicylic acid, two of its major metabolites, did not show similar effects. SSA exhibited an inhibitory effect on both mouse and rat mesangial cells but at rather higher concentrations (0.5 mM). Excretion of interleukin (IL)-8 by lipopolysaccharide (LPS)-stimulated PMN was also markedly deterred in a dose-dependent manner but excretion of IL-X by LPS-stimulated MNC was not interfered by SSA. Production of tumor necrosis factor (TNF)-alpha and IL- 1 beta by mouse mesangial cells was not blocked by SSA but production of IL- 4 by these cells was inhibited by it (>0.1 mM). Inhibition of MNC was not due directly to cytotoxic effect of SSA on these cells as shown by fluorescein diacetate stain. Collectively, SSA inhibits phagocytosis and IL-8 excretion by PMN as well as mitogen-stimulated MNC reaction. On the other hand, at high concentrations, it inhibits glomerular mesangial cells and their IL-4 excretion but not TNF-alpha and IL-1 beta excretion. These results can account for minimal nephrotoxic characteristic of SSA and suggest that it may be helpful in the treatment of immune-mediated glomerulonephritis. (C) 2000 Elsevier Science Inc. All rights reserved