Impact of interleukin-13 responsiveness on the synthetic and proliferative properties of Th1- and Th2-type pulmonary granuloma fibroblasts

Am J Pathol. 2003 May;162(5):1475-86. doi: 10.1016/S0002-9440(10)64280-0.

Abstract

Interleukin-13 (IL-13) has emerged as a major cytokine mediator of fibroblast activation and pulmonary fibrosis. Normal (from noninflamed lung), Th1-type (induced by the pulmonary embolization of purified peptide derivative-coated beads in mice sensitized to purified peptide derivative), and Th2-type (induced by the pulmonary embolization of Schistosoma mansoni egg antigen-coated beads in mice sensitized with S. mansoni eggs) primary fibroblast cell lines all exhibited constitutive gene expression of two receptor chains that bind and signal IL-13-mediated cellular events: IL-4Ralpha and IL-13Ralpha1. However, all three fibroblast cell lines exhibited divergent synthetic and proliferative responses to the exogenous addition of either recombinant IL-13 or a chimeric protein comprised of IL-13 and a truncated version of Pseudomonas exotoxin (IL13-PE), which targets and kills IL-13 receptor overexpressing cells. The exogenous addition of IL-13 to Th1-type and Th2-type fibroblast cultures significantly increased the cellular expression of IL-13Ralpha2, which may function as an IL-13 decoy receptor. After a 24-hour exposure to IL-13, the total collagen generation and cellular proliferation by Th2-type fibroblasts were significantly higher than that observed in similar numbers of normal and Th1-type fibroblasts. In addition IL13-PE, which binds with highest affinity to IL-13Ralpha2, exhibited down-regulatory effects on proliferation and matrix generation expression by Th1- and Th2-type, but not normal, fibroblasts. Thus, these data demonstrate that fibroblasts derived from murine pulmonary granulomas exhibit divergent expression of functional IL-13 receptor and this expression dictates the responsiveness and susceptibility to recombinant IL-13 and IL-13 immunotoxin, respectively.

Publication types

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

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Cells, Cultured
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / immunology
  • Fibroblasts / pathology
  • Gene Expression Regulation / drug effects
  • Interleukin-13 / pharmacology*
  • Interleukin-13 Receptor alpha1 Subunit
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred CBA
  • Plasma Cell Granuloma, Pulmonary / immunology*
  • Plasma Cell Granuloma, Pulmonary / pathology*
  • Receptors, Interferon / analysis
  • Receptors, Interleukin / analysis
  • Receptors, Interleukin-13
  • Th1 Cells / immunology*
  • Th2 Cells / immunology*

Substances

  • Il13ra1 protein, mouse
  • Interleukin-13
  • Interleukin-13 Receptor alpha1 Subunit
  • Receptors, Interferon
  • Receptors, Interleukin
  • Receptors, Interleukin-13
  • interferon gamma receptor