Abstract
BackgroundDysregulated production of cytokines has a critical role in systemic lupus. The aim of this work is to identify, by a comprehensive analysis of IL-1 family cytokines and receptors in serum, correlation between cytokines/receptors’ levels and the clinical and serological features of the disease.MethodsA full clinical evaluation was performed in 74 patients with systemic lupus erythematosus (SLE). C3, C4, anti-dsDNA and anti-C1q antibodies were measured. Cytokines of the IL-1 family (IL-1α, IL-1β, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, ST2/sIL-1R4) and antagonists (IL-1Ra, IL-18 binding protein (IL-18BP)) were measured in serum by multiarray ELISA. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Data were analysed by non-parametric tests and by multivariate analysis, using partial least squares (PLS) models.ResultsTotal IL-18, IL-18BP, sIL-1R4 and IL-1Ra levels were higher in SLE vs. controls. Total and free IL-18 and sIL-1R4 were higher in patients with active vs. inactive disease and correlated with ECLAM, anti-C1q and anti-dsDNA antibodies. sIL-1R2 was higher in patients with inactive disease, was negatively correlated with ECLAM and anti-C1q antibodies and was positively correlated with C3 levels. PLS identified sIL-1R4, sIL-1R2 and anti-dsDNA as variables distinguishing patients with active from those with inactive disease; sIL-1R4, IL-18BP and anti-dsDNA identified patients with active nephritis; sIL-1R4, C3, IL-18 and free IL-18 identified patients with haematological involvement.ConclusionThe data support the use of IL-18, sIL-1R2 and sIL-1R4 as biomarkers of disease activity and organ involvement, and suggest that failure in the inhibition of IL-1 activation may be a critical event in the active stages of SLE.
Highlights
Dysregulated production of cytokines has a critical role in systemic lupus
Monocytes/macrophages and dendritic cells are the major source of IL-18, produced as precursor protein and enzymatically cleaved to give rise to the mature active cytokine [1]
Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18 binding protein (IL-18BP) [22]
Summary
Dysregulated production of cytokines has a critical role in systemic lupus. Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the production of a variety of autoantibodies directed against highly conserved molecules, mainly but not exclusively localised in the cell nucleus. Dysregulated production of a number of cytokines, including those of the IL-1 family, has a critical role in the disease, orchestrating this immune activation. Monocytes/macrophages and dendritic cells are the major source of IL-18, produced as precursor protein and enzymatically cleaved to give rise to the mature active cytokine [1]. IL-18 activity is regulated by IL-18 binding protein (IL-18BP), a soluble molecule that binds mature IL-18 with high affinity and prevents its interaction with cell surface receptors [2]. The level of free IL-18, which is able to interact with the membrane receptors and is biologically active, de-
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