Thymic stromal lymphopoetin-induced expression of the endogenous inhibitory enzyme SLPI mediates recovery from colonic inflammation

Immunity. 2011 Aug 26;35(2):223-35. doi: 10.1016/j.immuni.2011.05.015. Epub 2011 Aug 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / immunology*
  • Colitis / metabolism
  • Colon / drug effects
  • Colon / pathology
  • Dextran Sulfate / administration & dosage
  • Down-Regulation
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Immunity, Mucosal
  • Immunoglobulins / metabolism*
  • Inflammation
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Leukocyte Elastase / genetics
  • Leukocyte Elastase / immunology
  • Leukocyte Elastase / metabolism*
  • Mice
  • Mice, Knockout
  • Receptors, Cytokine / metabolism*
  • Recombinant Proteins / genetics
  • Secretory Leukocyte Peptidase Inhibitor / administration & dosage
  • Secretory Leukocyte Peptidase Inhibitor / genetics
  • Secretory Leukocyte Peptidase Inhibitor / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology

Substances

  • Immunoglobulins
  • Receptors, Cytokine
  • Recombinant Proteins
  • Secretory Leukocyte Peptidase Inhibitor
  • Slpi protein, mouse
  • Tslpr protein, mouse
  • Dextran Sulfate
  • Leukocyte Elastase