title: Signal transducer and activator of transcription (STAT) 3 inhibition delays the onset of lupus nephritis in MRL/lpr mice.
abstract: The transcription factor STAT3 is overexpressed and hyperactivated in T cells from SLE patients. STAT3 plays a central role in T cell differentiation into Th17 and T follicular helper cells, two subsets that orchestrate autoimmune responses in SLE. Moreover, STAT3 is important in chemokine-mediated T cell migration. To better understand its role in SLE, we inhibited STAT3 in lupus-prone mice using the small molecule Stattic. Stattic-treated mice exhibited delayed onset of proteinuria (3 weeks later than controls), and had lower levels of anti-dsDNA antibodies and inflammatory cytokines. Inhibitor treatment reduced lymphadenopathy, resulted in a 3-fold decrease in total T cell number, and a 4-fold decrease in the numbers of T follicular helper cells. In vitro experiments showed that Stattic-treated T cells exhibited decreased proliferation and a decrease in ability to migrate to CXCL12. We propose that STAT3 inhibition represents a therapeutic target in SLE, particularly lupus nephritis.
authors: Division of Rheumatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
authors: Lindsay J
authors: LJ
authors: Edwards
authors: Division of Rheumatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
authors: Masayuki
authors: M
authors: Mizui
authors: Division of Rheumatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA. Electronic address: vkyttari@bidmc.harvard.edu.
authors: Vasileios
authors: V
authors: Kyttaris
mesh_terms: D000818:Animals; D003499:Cyclic S-Oxides / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D007074:Immunoglobulin G / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D003499:Cyclic S-Oxides; D016207:Cytokines; D007074:Immunoglobulin G; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C517409:stattic
keywords: MRL/lpr; Murine lupus; SLE; STAT3; T cells