Date of Graduation
Master of Science in Cell and Molecular Biology
innate immune signaling, cytokines, gene expression, signal transduction, receptor crosstalk
Medical Molecular Biology
Lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor 4 (TLR4)-dependent signals leading to the expression of pro-inflammatory genes. Although important for a defensive response, this pro-inflammatory state must be kept in check to limit inflammation-associated tissue damage. IL-10 is an important anti-inflammatory cytokine that limits inflammatory responses; however, our understanding of how IL-10 acts remains incomplete. Previously ABIN-3 was identified as an IL-10-induced gene capable of inhibiting LPS/TLR4-signaling. Interestingly, induction of ABIN-3 by IL-10 depends on co-stimulation with LPS (IL-10 super-induced gene). Herein, I show that ABIN-3 is a secondary response gene whose expression depends on new protein synthesis. IL-10 appears to synergize with LPS to induce ABIN-3 expression at the level of transcription as opposed to inducing its mRNA stabilization. To determine whether the mechanisms controlling ABIN-3 gene expression extend to other genes, I performed a candidate gene screen. At the end of this screen, three distinct groups of IL-10 super-induced genes were identified in the monocyte/macrophage cell line THP-1. These groups are separated based on their kinetics of induction and dependence on new protein synthesis. A group of primary/early response genes including SOCS-3, JunB, DUSP1, RGS16, and PTX3 in addition to early and late secondary response gene groups which include CXCL13, IL-7R, S100A9, Cnx43, IL-1RA, RGL1, TNFR2, and CHI3L2.
© Brad Groppe
Groppe, Brad, "Characterization of Distinct Sequential Subsets of IL-10 Induced Genes in LPS-Triggered Human Monocytic Cells" (2011). MSU Graduate Theses. 1852.