Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling.
Bottom Line: Pep(-/-) hematopoietic progenitors demonstrate increased IFNAR signaling, increased IFN-inducible gene expression, and enhanced proliferation and activation compared to Pep(+/+) progenitors in response to IFN-α.In addition, Pep(-/-) mice treated with IFN-α display a profound defect in hematopoiesis, resulting in anemia, thrombocytopenia, and neutropenia when compared to IFN-α-treated Pep(+/+) mice.As SLE patients carrying the PTPN22(C1858T) risk variant have higher serum IFN-α activity, these data provide a molecular basis for how type I IFNs and PTPN22 may cooperate to contribute to lupus-associated cytopenias.
Affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.Show MeSH
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Mentions: Our data and that of others (Essers et al., 2009) suggest an intrinsic requirement for IFNAR signaling on progenitor cells during IFN-α–mediated disease and stress hematopoiesis. To determine the role of PEP in IFNAR signaling, lineage-depleted BM cells from Pep+/+ and Pep−/− mice were treated with IFN-α and STAT1 phosphorylation was assessed by Western blot using an anti–phospho-specific STAT1 antibody. Addition of recombinant mouse IFN-α4 (rIFN-α4) to Pep−/− progenitors demonstrated a twofold increase in STAT1 phosphorylation on tyrosine 701 compared to Pep+/+ progenitors (Fig. 5, A and B). Increased STAT1 phosphorylation was also observed using in vitro–generated Pep−/− myeloid progenitors (Fig. 5, C and D). To determine the downstream consequences of enhanced STAT phosphorylation in Pep−/− progenitor cells, we treated Pep+/+ and Pep−/− mice with poly(I:C) for 16 h and sorted lineage-negative progenitor cells for transcriptome analysis. Consistent with increased phosphorylation and activation of STAT1, IFN-responsive genes Isg15, Irf4, Mx1, and Osmr were significantly up-regulated in Pep−/− compared to Pep+/+ progenitor cells (Fig. 5 E and Table S1).
Affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.