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

Introduction Systemic 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. Methods Gene 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, IFN gamma, beta-estradiol (E2), and IFN alpha 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. Results Thirty-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 IFN gamma - 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 IFN alpha and one of TNF, IFN gamma, or E2 revealed that TNF has repressive effects while IFN gamma essentially has synergistic effects on IFI gene expressions in vitro. E2 showed variable effects on IFI gene expressions among three individuals. Conclusions TNF may repress the abnormal regulation by IFN alpha in SLE while IFN gamma may have a synergistic effect. Interactions between IFN alpha and one of TNF, IFN gamma, or E2 appear to be involved in the pathogenesis of SLE.