Contrasting roles of IL-12p40 and IL-12p35 in the development of hapten-induced colitis

Eur J Immunol. 2002 Jan;32(1):261-9. doi: 10.1002/1521-4141(200201)32:1<261::AID-IMMU261>3.0.CO;2-X.

Abstract

IL-12(p70), a heterodimer composed of two subunits (p35 and p40), is a key cytokine for Th1 mediated inflammatory responses. We dissected the role of IL-12 in the development of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis by studying mice deficient in IL-12p40, IL-12p35, or IL-12Rbeta1. TNBS-treated IL-12Rbeta1(-/-) and IL-12p35(-/-) mice developed only a mild disease associated with low level IL-18 expression in IL-12p35(-/-) mice. In contrast, IL-12p40(-/-) mice developed more severe colitis than wild-type mice associated with high level colonic IL-18 expression. Administration of IL-12p40 neutralizing mononuclear antibody dramatically increased pathology in IL-12p35(-/-) mice similar to disease scored in IL-12p40(-/-) mice. Numbers of IFN-gamma-producing cells infiltrating the lamina propria were comparably augmented in the different groups of IL-12-mutant and wild-type mice. These results demonstrate that IL-12p40, in contrast to IL-12p70, inhibits TNBS-induced colitis and IL-18 expression independent of IFN-gamma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basement Membrane / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Colon / pathology
  • Crohn Disease / chemically induced
  • Crohn Disease / immunology*
  • Crohn Disease / pathology
  • Disease Models, Animal
  • Female
  • Haptens / adverse effects
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology*
  • Interleukin-18 / genetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology
  • Receptors, Interleukin-12
  • T-Lymphocytes / immunology
  • Trinitrobenzenesulfonic Acid / adverse effects

Substances

  • Haptens
  • Interleukin-18
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • Interleukin-12
  • Interferon-gamma
  • Trinitrobenzenesulfonic Acid