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.
BACKGROUND
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, IFNgamma, beta-estradiol (E2), and IFNalpha 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 IFNgamma--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 IFNalpha and one of TNF, IFNgamma, or E2 revealed that TNF has repressive effects while IFNgamma 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 IFNalpha in SLE while IFNgamma may have a synergistic effect. Interactions between IFNalpha and one of TNF, IFNgamma, or E2 appear to be involved in the pathogenesis of SLE.
Lee
Hooi-Ming
HM
Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-Oka, Suita City, Osaka 565-0871, Japan. lhmvio82@fbs.osaka-u.ac.jp
Mima
Toru
T
Sugino
Hidehiko
H
Aoki
Chieko
C
Adachi
Yasuo
Y
Yoshio-Hoshino
Naoko
N
Matsubara
Kenichi
K
Nishimoto
Norihiro
N
D000328:Adult; D000368:Aged; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007370:Interferon Type I; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D007371:Interferon-gamma