Identificazione del ruolo di IL-18 nella patogenesi e nel danno d'organo in un modello murino di lupus

Interleukin 18 (IL-18) is an inflammatory cytokine produced mainly by monocytes/macrophages in response to microbial stimuli and is able to induce IFN-γ in Th1 and NK cells. IL-18 is present at increased levels in serum and in organs in patients with autoimmune and chronic inflammatory disorders (rheumatoid arthritis, Crohn’s disease, Sjögren syndrome, psoriasis and systemic lupus erithematosus), and it has been reported to correlate with disease activity. This suggests that this factor may have a pathological role in autoimmunity. However, it is unknown if IL-18 has a pathogenic role in autoimmune derangements, or if its increase is a consequence of the disorder. The aim of this study is to identify possible alterations in the expression of different molecules involved in the production and activity of IL-18, in order to better understand the role of IL-18 in autoimmune pathologies, and to clarify the molecular basis for enhanced IL-18 function in autoimmunity. The study was performed in a murine model of chronic progressive autoimmune syndrome, the MRL lpr/lpr mice. The lpr mutation is a null allele for fas, a member of the TNF family of receptors that signals for death of the immune system. Mice are born disease-free and exhibit the first autoimmune symptoms at 9-12 weeks of age. Thus, the murine model offers the possibility to follow the pathology throughout its progression. The gene expression levels were assessed for IL-18 and other molecules correlated to its production and signalling pathways: IL-18BP (natural inhibitor of IL-18), the two IL-18 receptor chains (IL-18Rα and IL-18Rβ), the inhibitory receptor TIR8/SIGIRR. It was also analysed the expression level of another cytokine of IL-1 family, IL-33, as well as of its receptor T1/ST2, its accessory protein IL-1RAcP and the orphan receptor TIGIRR-1. mRNA was extracted from various organs of mice between 5 and 26 weeks of age, and gene expression was measured by Real-Time PCR. Moreover, the concentration of free IL-18 was assessed by ELISA assays for IL-18 and IL-18BP. Preliminary data suggest that it is possible hypothesize a role for IL-18 in the organ-specific autoimmune pathogenesis, limited to the primary organ targets (such as lymph nodes). On the other hand, in organs that are affected at later stages in end-organ disease (such as lung or kidney) increased IL-18 correlates with disease severity and might be considered as a consequence of the de-regulated production of inflammatory cytokines caused by autoimmune alterations