Interactions among type I and type II interferon, tumor necrosis factor, and β-estradiol in the regulation of immune response-related gene expressions in systemic lupus erythematosus

Abstract

IntroductionSystemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by various clinical manifestations. Several cytokines interact and play pathological roles in SLE, although the etiopathology is still obscure. In the present study we investigated the network of immune response-related molecules expressed in the peripheral blood of SLE patients, and the effects of cytokine interactions on the regulation of these molecules.MethodsGene expression profiles of peripheral blood from SLE patients and from healthy women were analyzed using DNA microarray analysis. Differentially expressed genes classified into the immune response category were selected and analyzed using bioinformatics tools. Since interactions among TNF, IFNγ, β-estradiol (E2), and IFNα may regulate the expression of interferon-inducible (IFI) genes, stimulating and co-stimulating experiments were carried out on peripheral blood mononuclear cells followed by analysis using quantitative RT-PCR.ResultsThirty-eight downregulated genes and 68 upregulated genes were identified in the functional category of immune response. Overexpressed IFI genes were confirmed in SLE patient peripheral bloods. Using network-based analysis on these genes, several networks including cytokines – such as TNF and IFNγ – and E2 were constructed. TNF-regulated genes were dominant in these networks, but in vitro TNF stimulation on peripheral blood mononuclear cells showed no differences in the above gene expressions between SLE and healthy individuals. Co-stimulating with IFNα and one of TNF, IFNγ, or E2 revealed that TNF has repressive effects while IFNγ essentially has synergistic effects on IFI gene expressions in vitro. E2 showed variable effects on IFI gene expressions among three individuals.ConclusionsTNF may repress the abnormal regulation by IFNα in SLE while IFNγ may have a synergistic effect. Interactions between IFNα and one of TNF, IFNγ, or E2 appear to be involved in the pathogenesis of SLE.

Elevated plasma level of HMGB1 is associated with disease activity and combined alterations with IFN-alpha and TNF-alpha in systemic lupus erythematosus

“…Previous studies showed repressive effect of TNF-alpha on interferon-inducible gene expression [37,38], and the inverse correlation between TNF-alpha and IFN-alpha in HC should be a consequence of their cross regulation. However, unlike in HC, TNF-alpha may fail to regulate IFN-alpha production in SLE, and a combined increase of both cytokines can promote the pathogenesis [39].…”

Relationship between vitamin D, IFN-γ, and E2levels in systemic lupus erythematosus

“…16 Therefore, the possibility that E 2 plays a significant role in the pathophysiology of SLE cannot be excluded. 17 There is little information in the medical literature about a relationship between serum IFN-g, vitamin D, and E 2 levels in female SLE patients of reproductive age with inactive disease. Due to the known effects of these factors on the course of lupus disease and in order to better understand the etiopathogenesis of SLE, we explored the relationship between these factors specifically in patients with inactive disease to minimize confounding factors.…”

The new era of autoimmune disease research

“…Other studies have also reported increased expression of IFN-inducible genes (that is, the 'IFN signature') in peripheral blood cells from patients with SLE [2-4]. Many groups are currently looking into pathological roles of plasmacytoid dendritic cells (pDCs) and IFN-inducible genes in SLE since pDCs are major producers of IFN-α [4-7].…”