PROINFLAMMATORY CYTOKINES REGULATE FE-ALPHA-R EXPRESSION BY HUMAN MESANGIAL CELLS IN-VITRO

IgA nephropathy (IgAN) is defined by the predominant deposition of IgA immune complexes (IC) in the glomerular mesangium. Interaction betwee n IgA immune complexes and mesangial cells (MC) could be a linchpin fo r the genesis of IgAN. We studied the modulation of MC expression of I gA receptors (Fc alpha R) by selected cytokines. Binding of I-125-IgA to quiescent human MC showed 2.55 x 10(5) sites/cell with an affinity (Ka) of 3.2 x 10(7) M(-1). Addition of selected recombinant cytokines had no significant influence on Ka, but increased the number of sites/ cell relative to unstimulated cells. Northern hybridization using the pHuFc alpha R cDNA probe showed time-dependent increases in mRNA expre ssion in stimulated versus control cells. IL-6 and tumour necrosis fac tor-alpha (TNF-alpha) had a biphasic effect on the Fc alpha R mRNA lev el; at 48 h, IL-6 increased steady state mRNA levels about sin-fold re lative to control, TNF-alpha increased mRNA four-fold, and interferon- gamma (IFN-gamma) induced Fc alpha R mRNA twofold. By reverse transcri ptase-polymerase chain reaction (RT-PCR), the Fc alpha R expressed on human MC appears highly homologous to that expressed by U937 cells. Al tered Fc alpha R expression in response to cytokines may influence the pathogenesis of IgAN by affecting deposition and/or clearance of IgA- IC in the mesangium.