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.
Highlights
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by various clinical manifestations
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
Immune response-related genes identified by gene ontology analysis Thirty-eight downregulated genes and 68 upregulated genes were categorized into the functional category of immune response
Summary
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by various clinical manifestations. Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiple organ damage, high titers of autoantibodies, and various clinical manifestations [1]. An impaired production of IL-12 by T lymphocytes from SLE patients in vitro has been aRNA: amino allyl RNA; Ct: cycle threshold; E2: -estradiol; Fc R: Fc receptor; GBP: guanylate binding protein; HLA: human leukocyte antigen; IFI: interferon-inducible; IFIT: interferon-induced protein with tetratricopeptide repeats; IFN: interferon; IL: interleukin; IRF7: interferon regulatory factor 7; ISG15: interferon-stimulated gene, 15 kDa; MAPK: mitogen-activated protein kinase; MHC: major histocompatibility complex; NF B: nuclear factor of kappa light polypeptide; OAS1: 2',5'-oligoadenylate synthetase 1; OASL: 2',5'-oligoadenylate synthetase-like; PBMC: peripheral blood mononuclear cell; PCR: polymerase chain reaction; RT: reverse transcription; SLE: systemic lupus erythematosus; TLR: Toll-like receptor; TNF: tumor necrosis factor. Comprehending the pathological roles of these abnormally induced cytokines and immunoregulatory networks of cytokines in SLE patients is important so that appropriate treatment can be offered
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