An essential role for IFN-alpha in the overexpression of Fas ligand on MRL/lpr lymphocytes and on their spontaneous Fas-mediated cytotoxic potential.
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-alpha (IFN-alpha) 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-alpha, and 4 were strongly downregulated. MRL/lpr lymphocytes were also found to be hyperresponsive to IFN-alpha. Thus, MRL/lpr lymphocytes overexpressed mRNA for the IFN-alpha receptor (IFNAR-1 and IFNAR-2) chains of the IFN-alpha/beta 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-alpha. These data suggest that IFN-alpha plays an important role in the physiopathology of the systemic lupus erythematosus (SLE)-like syndrome that occurs in MRL/lpr mice.
Hadj-Slimane
Réda
R
Laboratoire d'Oncologie Virale, CNRS UPR 9045, Institut André Lwoff, Villejuif, France.
Chelbi-Alix
Mounira K
MK
Tovey
Michael G
MG
Bobé
Pierre
P
D000818:Animals; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018076:DNA, Complementary / Q000032:analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation; D016898:Interferon-alpha / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009693:Nucleic Acid Hybridization; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C508034:Ifnar2 protein, mouse; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D053633:Receptor, Interferon alpha-beta