IFNg in SLE and Other Autoimmune Diseases

Several lines of evidence implicate IFNy in inflammatory autoimmune disease (Billiau, 1996; Schwarting et al., 1998). First, signaling through the IFNy receptor is essential for the initiation and progression of lupus nephritis in lupus-prone, MRL-lprfas mice (Schwarting et al., 1998). Second, the IFNy-related transcription factor T-bet has been shown to regulate IgG2a class switching and induction of pathogenic autoantibodies in murine lupus (Peng et al., 2002). Third, during the course of SLE, the increased level and the expression of IFNy was accompanied by an increase in IgG2a and IgG3 levels (Reininger et al., 1996). Fourth, in the absence of IFNy gene, the levels of anti-dsDNA and ss-DNA autoantibodies, and immune complex-mediated glomerulonephritis are decreased in murine models of SLE (Carvalho-Pinto et al., 2002). Fifth, blocking IFNy by the administration of plasmids with cDNA encoding the IFNy-receptor Fc into MRL-lpr mice (at preclinical or advanced stages of lupus) resulted in decreased IFNy levels in the sera and decreased hallmarks of lupus, such as autoantibodies, hyperplasia, glomerulonephritis, and mortality (Lawson et al., 2000). Sixth, addition of estrogen to CD4+ T cell lines from MS patients results in increased production of IFNy and IL-10 (Gilmore etal., 1997). Finally, in the absence of the IL-12p40 gene, the IFNy levels are decreased in lupus patients and the survival is increased (Kikawada et al., 2003).

In several strains of mice including non-autoimmune (C57BL/6J, CBA/Ca) and autoimmune (B/W) mice, females secrete more IFNy compared to males (Huygen and Palfliet, 1983; Haas et al, 1998; Karpuzoglu-Sahin et al, 2001). Transcription of the IFNy gene was also increased in unstimulated T cells from females of the B/W strain of mice (Sato et al., 1995). Studies from our laboratory have shown that several estrogenic compounds (17P-estradiol, DES, genistein, a-zeralanone) influence the transcription of the IFNy gene or the levels of IFNy protein (Karpuzoglu-Sahin et al., 2001; Calemine et al., 2003). In the case of 17P-estradiol, splenocytes from estrogen-treated C57BL/6 mice, when activated with T cell mitogens, had increased IFNy gene expression and higher levels of IFNy. In this strain, estrogen had no marked effect on IL-4 mRNA or protein levels. Estrogen treatment of CD-1 mice also increased IFNy mRNA expression in Concanavalin-A-stimulated splenocytes (Fox et al., 1991). Culturing of PBMC from nonpregnant women with estrogen increased IFNy secretion compared to similar cultures from men (Grasso and Muscettola, 1990). Administration of physiological doses of 17P estradiol to castrated female mice results in the selec tive development of IFNy-producing cells from the lymph nodes (Maret et al., 2003). ERa, but not ERp, was necessary for enhanced estrogen-driven Th1 cell responsiveness (Maret et al., 2003).

0 0

Post a comment