title: Thymic stromal lymphopoetin-induced expression of the endogenous inhibitory enzyme SLPI mediates recovery from colonic inflammation.
abstract: Thymic stromal lymphopoetin (TSLP) influences numerous immune functions, including those in the colonic mucosa. Here we report that TSLP-deficient (Tslp(-/-)) mice did not exhibit increased inflammation during dextran sodium sulfate (DSS)-induced colitis but failed to recover from disease, resulting in death. Increased localized neutrophil elastase (NE) activity during overt inflammation was observed in Tslp(-/-) mice and was paralleled by reduced expression of an endogenous inhibitor, secretory leukocyte peptidase inhibitor (SLPI). Pharmacological inhibition of NE or treatment with rSLPI reduced DSS-induced mortality in Tslp(-/-) mice. Signaling through TSLPR on nonhematopoietic cells was sufficient for recovery from DSS-induced colitis. Expression of the receptor occurred on intestinal epithelial cells (IEC), with stimulation inducing SLPI expression. Therefore, TSLP is critical in mediating mucosal healing after insult and functions in a nonredundant capacity that is independent of restraining T helper 1 (Th1) and Th17 cell cytokine production.
authors.affiliation: The Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Colin
authors.initials: C
authors.lastname: Reardon
authors.forename: Matthias
authors.initials: M
authors.lastname: Lechmann
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.forename: Mélanie G
authors.initials: MG
authors.lastname: Gareau
authors.forename: Naomi
authors.initials: N
authors.lastname: Shuman
authors.forename: Dana
authors.initials: D
authors.lastname: Philpott
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000473:pathology; D016264:Dextran Sulfate / Q000008:administration & dosage; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D018928:Immunity, Mucosal; D007136:Immunoglobulins / Q000378:metabolism*; D007249:Inflammation; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019272:Leukocyte Elastase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018121:Receptors, Cytokine / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D007136:Immunoglobulins; D018121:Receptors, Cytokine; D011994:Recombinant Proteins; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; C410591:Tslpr protein, mouse; D016264:Dextran Sulfate; D019272:Leukocyte Elastase