Abstract
Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of glomerular disease. Using an acute model of mesangial proliferative glomerulonephritis (Thy1 GN), we show that neutralization of interleukin (IL)-10 greatly ameliorated the disease as expressed by both decreased MC expansion and proteinuria. Treatment with the tellurium compound AS101 (ammonium trichloro(dioxoethylene-o,o')tellurate) resulted in favorable effects provided that the compound was administered 24 h before insult, whereas partial effects were obtained when administered after insult. We identified STAT3 as playing a pivotal role in IL-10-induced MC proliferation in vitro and in vivo. IL-10 activates MC STAT3 in vitro as expressed by its phosphorylation and nuclear translocation. The role of STAT3 in MC proliferation induced by IL-10 was deduced from results showing that IL-10-induced proliferation was abrogated if MC transfected with STAT3 antisense oligonucleotides were used or if cells were incubated with inhibitors of STAT3. AS101 deactivates STAT3 in control but not in MC transfected with IL-10 antisense oligonucleotides. Inactivation of STAT3 prevents reduction of MC proliferation by AS101. We further demonstrate the role of STAT3 in the regulation of cell cycle and survival regulatory proteins by AS101 in MC via inhibition of IL-10. IL-10 increased MC expression of Bcl-2 and Bcl-X1 and simultaneously decreased the levels of p27kip1. These survival factors were decreased by AS101 in a STAT3- and IL-10-dependent manner, whereas p27kip1 was similarly increased. In Thy1 GN, phosphorylated STAT3 in glomerular MC peaked at day 6 and correlated with MC expansion. Neutralization of IL-10 or its inhibition by AS101 abolished phosphorylation of STAT3. This effect positively correlated with amelioration of the disease. These in vitro and in vivo studies indicate that the autocrine MC growth factor IL-10 induces MC proliferation via STAT3. We suggest that IL-10 or its downstream target STAT3 might be therapeutic targets for kidney diseases induced by mesangial proliferation.
Highlights
Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of glomerular disease
The results show that treatment with the anti-IL-10 compound AS101 starting 24 h before anti-Thy1 administration greatly ameliorated the disease, decreasing the level of activated mesangial cell expansion to that seen in normal rats (c and c1)
Treatment with AS101 or Anti-IL-10 Antibodies Deactivates Mesangial STAT3 in Vivo—Because AS101-mediated inhibition of mesangial cell proliferation appears to depend on suppression of IL-10-mediated STAT3 activation in vitro, we examined the role of STAT3 in the decreased MC expansion observed in rats treated with AS101 or anti-IL-10 Abs in vivo glomerular proteins collected at days 0, 2, 4, and 6 after Thy1 administration revealed a gradual increase in phosphorylated STAT3, which peaked at day 6 (Fig. 8A)
Summary
Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of glomerular disease. Neutralization of IL-10 or its inhibition by AS101 abolished phosphorylation of STAT3 This effect positively correlated with amelioration of the disease. These in vitro and in vivo studies indicate that the autocrine MC growth factor IL-10 induces MC proliferation via STAT3. The STATs comprise a family of functionally related proteins that play key roles in a variety of biological activities such as cell differentiation and proliferation. They exert their activities through cytokine and growth factor receptors and are believed to be involved in determining the biological specificity of specific cytokines on various target tissues [9]. In a murine model of septic peritonitis, AS101 was recently shown to prevent kidney damage of septic mice [20]
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