Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair

J Immunol. 2003 Oct 1;171(7):3655-67. doi: 10.4049/jimmunol.171.7.3655.

Abstract

T helper 1 responses are typically proinflammatory, while Th2 responses have been considered regulatory. Interestingly, Th2 responses characterize a number of pulmonary diseases, many of which terminate in tissue remodeling and fibrosis. We developed a mouse model using Schistosoma mansoni eggs and cytokine-deficient mice to induce highly polarized Th1- or Th2-type inflammation in the lung. In this study, we examined the pathology and cytokine profiles in Th1- and Th2-polarized environments and used oligonucleotide microarray analysis to decipher the genes responsible for these effects. We further elaborated on the results using IL-10- and IL-13-deficient mice because these cytokines are believed to be the central regulators of Th2-associated pathology. We found that the Th1-polarized mice developed small granulomas with less fibrosis while expressing genes characteristic of tissue damage. Th2-polarized mice, in contrast, formed large granulomas with massive collagen deposition and up-regulated genes associated with wound healing, specifically, arginase, collagens, matrix metalloproteinases (MMPs), and tissue inhibitors of MMP. In addition, several members of the chitinase-like family were up-regulated in the lung following egg challenge. We also developed a method of defining the net collagen deposition using the expression profiles of several collagen, MMP, and tissue inhibitors of MMP genes. We found that Th1-polarized mice did not elaborate collagens or MMPs and therefore did not have a significant capacity for repair in this model. Thus, Th1-mediated inflammation is characterized by tissue damage, while Th2 directs wound healing and fibrosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Animals
  • Antigens, Helminth / administration & dosage
  • Antigens, Helminth / immunology
  • Cells, Cultured
  • Chitinases / biosynthesis
  • Chitinases / genetics
  • Cytokines / biosynthesis
  • Extracellular Matrix Proteins / biosynthesis
  • Extracellular Matrix Proteins / genetics
  • Gene Expression Profiling* / methods
  • Immunophenotyping
  • Lung Diseases, Parasitic / genetics
  • Lung Diseases, Parasitic / immunology*
  • Lung Diseases, Parasitic / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis / methods
  • Ovum / immunology
  • Schistosoma mansoni / immunology
  • Schistosomiasis mansoni / genetics
  • Schistosomiasis mansoni / immunology*
  • Schistosomiasis mansoni / pathology*
  • Species Specificity
  • Th1 Cells / enzymology
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th1 Cells / parasitology
  • Th2 Cells / enzymology
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism
  • Th2 Cells / parasitology
  • Up-Regulation / genetics
  • Up-Regulation / immunology
  • Wound Healing / genetics
  • Wound Healing / immunology*

Substances

  • Antigens, Helminth
  • Cytokines
  • Extracellular Matrix Proteins
  • Chitinases