title: Non-Hematopoietic β-Arrestin1 Confers Protection Against Experimental Colitis.
abstract: β-Arrestins are multifunctional scaffolding proteins that modulate G protein-coupled receptor (GPCR)-dependent and -independent cell signaling pathways in various types of cells. We recently demonstrated that β-arrestin1 (β-arr1) deficiency strikingly attenuates dextran sodium sulfate (DSS)-induced colitis in mice. Since DSS-induced colitis is in part dependent on gut epithelial injury, we examined the role of β-arr1 in intestinal epithelial cells (IECs) using a colon epithelial cell line, SW480 cells. Surprisingly, we found that knockdown of β-arr1 in SW480 cells enhanced epithelial cell death via a caspase-3-dependent process. To understand the in vivo relevance and potential cell type-specific role of β-arr1 in colitis development, we generated bone marrow chimeras with β-arr1 deficiency in either the hematopoietic or non-hematopoietic compartment. Reconstituted chimeric mice were then subjected to DSS-induced colitis. Similar to our previous findings, β-arr1 deficiency in the hematopoietic compartment protected mice from DSS-induced colitis. However, consistent with the role of β-arr1 in epithelial apoptosis in vitro, non-hematopoietic β-arr1 deficiency led to an exacerbated colitis phenotype. To further understand signaling mechanisms, we examined the effect of β-arr1 on TNF-α-mediated NFκB and MAPK pathways. Our results demonstrate that β-arr1 has a critical role in modulating ERK, JNK and p38 MAPK pathways mediated by TNF-α in IECs. Together, our results show that β-arr1-dependent signaling in hematopoietic and non-hematopoietic cells differentially regulates colitis pathogenesis and further demonstrates that β-arr1 in epithelial cells inhibits TNF-α-induced cell death pathways.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan.
authors.forename: Taehyung
authors.initials: T
authors.lastname: Lee
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan.
authors.forename: David
authors.initials: D
authors.lastname: Arrollo
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Lucas
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan.
authors.forename: Narayanan
authors.initials: N
authors.lastname: Parameswaran
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D016264:Dextran Sulfate; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D055785:Gene Knockdown Techniques; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007422:Intestines / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C000605255:Arrb1 protein, mouse; D019390:Arrestins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D016264:Dextran Sulfate; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8