Paraoxonase-1 suppresses experimental colitis via the inhibition of IFN-γ production from CD4 T cells

J Immunol. 2013 Jul 15;191(2):949-60. doi: 10.4049/jimmunol.1201828. Epub 2013 Jun 14.

Abstract

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, where excessive Th1 cell responses are observed. We performed experiments to identify immunologically bioactive proteins in human plasma and found that paraoxonase (PON)-1, which has esterase activity and is associated with high-density lipoproteins, inhibited the IFN-γ production by both murine and human differentiating Th1 cells. Trinitrobenzene sulfonic acid-induced colitis was attenuated by the administration of PON-1. The beneficial effects of PON-1 were associated with a reduced ratio of IFN-γ-producing CD4 T cells in the mesenteric lymph nodes and decreased production of T cell-related cytokines in the colon. PON-1 inhibited the TCR-induced activation of ERK-MAPK signaling and the nuclear translocation of NF-κB in CD4 T cells. Interestingly, an excessive CD4 T cell response was observed in PON-1-deficient mice under physiological and pathological conditions. Additionally, the efficacy of PON-1 or G3C9-C284A (G3C9), which shows a higher esterase activity than PON-1, on colitis was similar to that of an anti-TNF-α mAb, which is a clinically used CD treatment. Moreover, G3C9 more effectively suppressed CD4(+)CD45RB(high) cell transfer-induced chronic colitis in mice than did PON-1, and the efficacy of G3C9 against the colitis was similar to that of the anti-TNF-α mAb. Therefore, PON-1 (or G3C9) administration may be clinically beneficial for CD patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / immunology
  • Aryldialkylphosphatase / genetics
  • Aryldialkylphosphatase / metabolism*
  • Aryldialkylphosphatase / pharmacology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CHO Cells
  • Cell Differentiation
  • Cell Line
  • Colitis / chemically induced
  • Colitis / drug therapy*
  • Colitis / immunology
  • Colitis / metabolism
  • Colon / metabolism
  • Colon / pathology
  • Cricetinae
  • Crohn Disease / drug therapy*
  • Crohn Disease / immunology
  • Crohn Disease / metabolism
  • Female
  • Humans
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / metabolism*
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, SCID
  • NF-kappa B / metabolism
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Trinitrobenzenesulfonic Acid
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Antibodies, Monoclonal
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Trinitrobenzenesulfonic Acid
  • Aryldialkylphosphatase
  • PON1 protein, human