An Essential Role for IFN-α in the Overexpression of Fas Ligand on MRL/lprLymphocytes and on Their Spontaneous Fas-Mediated Cytotoxic Potential

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Abstract
Lymphocytes from aged autoimmune MRL/lpr mice overexpress Fas ligand (FasL), and are cytotoxic against Fas+ target cells. This cytotoxic potential is only partly due to FasL, as wild-type MRL+/+ lymphocytes are not able to kill Fas+ targets after induction of FasL. In addition, serum levels of interferon-α (IFN-α) increase in parallel with the Fas-dependent cytotoxic potential of lymphocytes from MRL/lpr mice as they age. To understand the mechanisms underlying these observations, combined suppression subtractive hybridization (SSH) and RT-PCR were used to study differential gene expression in splenocytes from MRL/lpr mice compared with splenocytes from MRL+/+ mice. Twenty-two genes were upregulated transcriptionally in MRL/lpr splenocytes compared with their MRL+/+ counterparts. Furthermore, 9 of these genes were also upregulated after treatment of MRL/lpr splenocytes with IFN-α, and 4 were strongly downregulated. MRL/lpr lymphocytes were also found to be hyperresponsive to IFN-α. Thus, MRL/lpr lymphocytes overexpressed mRNA for the IFN-α receptor (IFNAR-1 and IFNAR-2) chains of the IFN-α/β receptor and exhibited high endogenous levels of both Stat1 and phosphorylated Stat1 proteins. Lymphocytes from young MRL/lpr mice, with low Fas-dependent cytotoxic activity, were found to become highly cytotoxic against Fas+ targets after treatment with IFN-α. These data suggest that IFN-α plays an important role in the physiopathology of the systemic lupus erythematosus (SLE)-like syndrome that occurs in MRL/lpr mice.