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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Colitis / chemically induced
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Colitis / genetics
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Colitis / immunology*
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Colitis / metabolism
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Colon / drug effects
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Colon / pathology
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Dextran Sulfate / administration & dosage
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Down-Regulation
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Immunity, Mucosal
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Immunoglobulins / metabolism*
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Inflammation
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / immunology
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Intestinal Mucosa / metabolism*
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Intestinal Mucosa / pathology
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Leukocyte Elastase / genetics
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Leukocyte Elastase / immunology
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Leukocyte Elastase / metabolism*
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Mice
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Mice, Knockout
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Receptors, Cytokine / metabolism*
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Recombinant Proteins / genetics
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Secretory Leukocyte Peptidase Inhibitor / administration & dosage
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Secretory Leukocyte Peptidase Inhibitor / genetics
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Secretory Leukocyte Peptidase Inhibitor / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology
Substances
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Immunoglobulins
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Receptors, Cytokine
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Recombinant Proteins
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Secretory Leukocyte Peptidase Inhibitor
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Slpi protein, mouse
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Tslpr protein, mouse
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Dextran Sulfate
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Leukocyte Elastase