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Abstract: TH-PO809

GWAS-Follow-Up Study Identified Abnormal LIF Signaling Network Involving STAT1 and Src Family Protein-Tyrosine Kinases in IgA1-Secreting Cells from Patients with IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Yamada, Koshi, University of Alabama at Birmingham, Birmingham, United States
  • Huang, Zhi qiang, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Raska, Milan, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Reily, Colin, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Anderson, Joshua Charles, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Suzuki, Hitoshi, University of Alabama at Birmingham, Birmingham, United States
  • Kiryluk, Krzysztof, Columbia University, New York, New York, United States
  • Gharavi, Ali G., Columbia University, New York, New York, United States
  • Julian, Bruce A., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Willey, Christopher D., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Novak, Jan, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Genome-wide association studies (GWAS) in IgA nephropathy (IgAN) provide insight into disease pathobiology by identifying genetic loci and mapping the associated molecular pathways. A GWAS locus on chr. 22q12 encompasses genes that include LIF that encodes leukemia inhibitory factor, an IL-6-related cytokine implicated in mucosal immunity and inflammation. In this study, we characterized LIF signaling pathways leading to overproduction of galactose-deficient IgA1 (Gd-IgA1), using IgA1-secreting cell lines derived from peripheral blood of patients with IgAN and healthy controls (HC).

Methods

IgA1 was determined by ELISA, Gd-IgA1 lectin ELISA with Helix aspersa lectin. To assess LIF signaling pathways, we used global protein-tyrosine kinases (PTKs) activity profiling, immunoblotting, siRNA knock-down, and a JAK2 inhibitor.

Results

LIF activated STAT1 phosphorylation (Y701) to a greater level in IgA1-secreting cells from patients with IgAN (n=5) compared with those from HC (n=5) (p<0.01). LIF-mediated increase in Gd-IgA1 production by IgA1-secreting cells from patients with IgAN were reduced by siRNA STAT1 knock-down (p<0.05). Use of a JAK2 inhibitor revealed that this enhanced phosphorylation of STAT1 in IgA1-secreting cells from patients with IgAN was not mediated by JAK2. PTK activity profiling indicated that LIF signaling activated Src family of PTKs, based on highest kinase statistics (Kstat) and specificity.

Conclusion

LIF induced abnormal STAT1 signaling and enhanced production of Gd-IgA1 in IgA1-secreting cells from patients with IgAN, providing possible explanation for the phenotype associated with a GWAS locus encompassing LIF. Moreover, our exploratory data indicate involvement of Src family PTKs in LIF signaling that needs to be further explored.

Funding

  • NIDDK Support