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Abstract
Objective Lupus nephritis (LN) is a common and severe manifestation of the autoimmune disease systemic lupus erythematosus (SLE). Since LN-flares result in irreversible tissue damage, and thus may lead to renal failure, there is an urgent need to develop new therapeutic approaches. Therefore, we evaluated the disease promoting function of IL-28 Receptor Signals (IFNlambdaReceptor, the type III Interferon Receptor) in murine LN. Moreover, we determined the expression of type III Interferons (IL-28/IL-29) in LN patients to further explore their role in human LN.
Methods Progression of LN as well as systemic autoimmune symptoms were observed in IL-28R Knockout (KO) MRL-Faslpr lupus mice and compared to WT littermates. Furthermore, MRL-Faslpr mice were treated with a neutralizing anti IL-28 antibody. In LN patients, the IL-28/IL-29 expression was determined via IHC in renal biopsies. Additionally their expression in blood and urine samples was tested via ELISA. The activation of renal tubular epithelial cells (TEC) was examined in vitro.
Results A decelerated progression of LN was observed in IL-28R KO MRL-Faslpr mice. Moreover, Lymphadenopathy and serum antibodies were reduced and the progression of Sialadenitis was less severe. The disease promoting role of IL-28 was further confirmed by therapeutic treatment of MRL-Faslpr mice with an anti IL-28 antibody. The expression of IL-28/29 and as well as their receptor (IL-28R) was observed in renal biopsies of LN patients. The urine IL-29 levels in LN patients decreased during roughly one year after diagnosis/flare, while the C3c levels increased and the proteinuria tended to decrease. The expression of pro-inflammatory mediators by renal TEC after stimulation with type III Interferons was observed in vitro.
Conclusion The inhibition of IL-28R signals resulted in a less severe LN in MRL-Faslpr mice. Therefore and regarding our findings in human LN, we conclude that IL-28 inhibition should be considered as a therapeutic target for LN. Moreover, we suggest to further evaluate urine IL-29 as potential disease activity marker.
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