Activation of the STAT1 signalling pathway in lupus nephritis in MRL/lpr mice

Interferons (IFNs), type I (alpha/beta) and type II (gamma), comprise a family of multifunctional cytokines with antiviral. anti proliferative and immunomodulating properties. Both type I and type II IFNs have been heavily implicated in the pathogenesis of systemic lupus erythematosus (SLE). The biological effects of IFNs are mediated through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in which both IFN-alpha/beta and IFN-gamma activate the transcription factor STATI. However. little is known about the pathogenic significance of STATI in SLE. At this point, we examined the expression and activation of STAT I in the kidney of MRL/lpr mice with lupus nephritis (LN) by immunohistochemistry, Western botting and real time quantitative RT-PCR. Increased levels of total STAT I protein and its activated/phosphorylated form were detected in kidney samples from MRL/lpr mice with LN as compared to those from control mice. Phosphorylated STATI was predominantly detected in glomeruli cells. Gene expression of the STAT induced feedback inhibitors suppressor of cytokine signalling-1 (SOCS-1) and SOCS-3 was also enhanced in MRL/lpr mice. In MRL/lpr-mesangial cells, both IFN-alpha and IFN-gamma-rapidly induced the phosphorylation of STAT1 in vitro. Our results demonstrate that expression and activation of STAT1 are significantly increased in murine lupus nephritis, and indicate that STAT1 signalling pathway may play an important role in the pathogenesis of kidney inflammation.