Regulation of the JAK2/STAT3 Signaling Pathway by the Lupus Susceptibility Gene Pbx1

Abstract

Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease in which poorly characterized genetic factors lead to the production of autoreactive or inflammatory T cells. Pre-B cell leukemia homeobox 1 (Pbx1) is a transcription factor whose dominant negative splice isoform (Pbx1-D) is overexpressed in CD4 T cells of lupus patients and lupus-prone mice as compared to the normal isoform (Pbx1-B). Pbx1-D overexpression impairs Treg cell development and function while favoring the production of follicular helper T cells. Based on previous studies showing that Pbx1 promotes cell proliferation via JAK2/STAT3 signaling pathway in a renal cell carcinoma, we hypothesized that Pbx1-D decreases T cell proliferation and viability by attenuating the JAK2/STAT3 signaling pathway. Pbx1-B or Pbx1-D expression plasmids increased pSTAT3 protein levels but there was no difference between the two isoforms in 293T cells. U3A STAT3 reporter cells transfected with Pbx1-B plasmid have greater luciferase expression, and hence pSTAT3 transcriptional activity in comparison to cells transfected with Pbx1-D or control plasmids. We also observed that Pbx1-B increases the expression of Jak2 and Stat3 message as compared to Pbx1-D. These results suggest a mechanism by which Pbx1 contributes to impaired T cells in lupus pathogenesis is via the JAK2/STAT3 pathway. Current studies are conducted to dissect the mechanism by which Pbx1 regulates this pathway in primary T cells. Supported by a grant from the NIH (RO1AI04505021) to LM