Cytokines in systemic lupus erythematosus: far beyond Th1/Th2 dualism lupus: cytokine profiles

Abstract

The aims of this study were to delineate cytokine profiles of systemic lupus erythematosus (SLE), construct prediction models for diagnosis and disease activity using those profiles, and to examine the associations between TNFB Ncol polymorphism, body mass index (BMI) and vitamin D levels with cytokine levels. Two hundred SLE patients and 196 healthy controls participated in this case-control study. Plasma cytokines levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1β, IL- 4, IL-6, IL-10, IL-12 and IL-17 were measured and cytokines profiles were computed. IL-6, IL-12, IL-17, IFN-γ and IL-10 levels were significantly higher in SLE, while IL-4 was lower in SLE. The Th1/Th2 and Th1+Th17/Th2 profiles were significantly higher in SLE than in healthy controls, whereas there were no significant differences in the proinflammatory cytokine profile (TNFα+IL-6+IL-1β). In total, 90.4% of all subjects were correctly classified using Th1+Th17 profile and IL-10 (positively associated) and IL-4 (negatively associated) as predictor variables (sensitivity=66.7% and specificity=96.9%). In all, 20.9% of the variance in the SLE Disease Activity Index was predicted by the Th1+Th17/Th2 ratio, IL-10 and BMI (all positively) and proinflammatory profile (inversely associated). B1/B1 genotype is accompanied by increased IL-17 and Th17/Th2 ratio, while B1/B2 genotype is accompanied by higher IL-4 and IFNγ values. 25-OH vitamin D was inversely associated with IFN-γ levels. SLE is accompanied by Th1, Th17 and Treg profile and lowered IL-4 production. Lowered vitamin D levels and B1/B1 genotype, but not BMI, contribute to changes in cytokines profiles. Future treatments should target Th1, Th2 and Th17 profiles rather than inflammatory cytokines.

Vitamin D pathway activation selectively deactivates signal transducer and activator of transcription (STAT) proteins and inflammatory cytokine production in natural killer leukemic large granular lymphocytes

“…IFN-γ is a pro-inflammatory cytokine that is associated with worse disease state in multiple malignancies and autoimmune disorders [29–31]. IL-10 is classically known as an anti-inflammatory cytokine, but recent work has shown it has pro-inflammatory properties [32–34]. Flt-3L levels can be elevated in hematological malignancies and autoimmune diseases [35–38].…”

“…Vitamin D treatment increased IL-10 production in T cells, reprogramming them to a less inflammatory T-helper 2 cell type [12]. However, more recent data have suggested that IL-10 may have pro-inflammatory properties [32–34]. It is also a known transcriptional target of STAT3 and can positively regulate STAT3 signaling [49].…”

Biological Features of IL-12 and IFN-? in the Pathogenesis of Systematic Lupus Erythematosus

“…Some studies demonstrated that IL-12 was upregulated in serum of patients at the active stage of SLE, while others reported defective IL-12 production in lupus patients [36,42]. As for IFN-γ, divergences were not so obvious and past literatures tend to suggest that serum levels of IFN-γ were higher in lupus patients than in controls [10][11][12][13][14][15]. In addition, IFN-γ was also associated with symptomatology of SLE, in which a subtle correlation was found between SLEDAI scores and serum IL-4/IFN-γ ratios and evident correlation of IFN-γ with SLAM scores was also documented [16,17].…”

“…The damages of diverse organ and tissue are caused by different immune responses in SLE. The hormonal factors closely related to capillary damage in glomeruli, lungs, dermal tissues while damage for interstitium of kidneys, lacrimal, and salivary glands were caused by cell-mediated immunity [66,67]. Therefore, investigators thought single cytokinetargeted therapy might not be adequate because of complex cytokine network but a certain cytokine targeted therapy had potent effects with cascade reaction of immune response.…”

“…IFN-γ is a typical kind of cytokine secreted by Th1 cell and its expression profile is regulated by a series of IFNinducing factors including IL-12, IL-15 and IL-18. It was reported that serum levels of IFN-γ in lupus patients were higher than in controls [11][12][13][14]. Min et al investigated the associations between IFN-γ and lupus nephritis, and defective IFN-γ production was observed in 17 patients with lupus nephritis compared with 23 patients with unnephritic lupus.…”