Silencing allergic inflammation

Researchers reveal a new step in the regulation of allergic mediators

New work by Japanese scientists shows that a family of DNA-binding complexes prevents secretion of factors that trigger allergic inflammation. These complexes, which consist of so-called Runx proteins that bind to specific DNA sequences and the Cbfβ protein, exert anti-allergic effects in immune cells called helper T lymphocytes.

During immune responses, T lymphocytes acquire the capacity to produce different types of soluble factors called cytokines. Type 1 (TH1) cytokines help eradicate intracellular bacteria and viruses, but if not controlled can exacerbate autoimmune diseases. Type 2 (TH2) cytokines help combat extracellular bacteria and parasites, but when produced in excess can worsen allergies and asthma.

T lymphocytes produce either TH1 or TH2 cytokines. These mutually exclusive cellular ‘fates’ are shaped and maintained by distinct sets of transcription factors that bind to DNA sequences that are dedicated to enhancing or silencing expression of individual cytokine genes.

A team led by Ichiro Taniuchi, a scientist at the RIKEN Research Center for Allergy and Immunology in Yokohama, has determined that Runx complexes, which dampen expression of other genes in T lymphocytes, bind to and activate the silencer of Il4, a TH2 cytokine gene. Their findings were published in a recent issue of The Journal of Experimental Medicine1.

Using gene-targeting techniques, the researchers generated mice lacking either Runx3, or Cbfβ, specifically in T lymphocytes. Mice lacking CBFβ exhibited spontaneous lung infiltration (Fig. 1). Mice lacking Runx3 displayed milder versions of these asthma-like symptoms.

Incubation with TH1-promoting cytokines ‘skews’ naive T cells towards a TH1 fate and silences TH2 cytokine gene expression. CBFβ-mutant T cells, and, to a lesser extent their Runx3-deficient counterparts, were resistant to TH1 polarization and failed to suppress TH2 cytokine production.

Runx complexes bind directly to the Il4 silencer in un-polarized T cells and TH1 cells, but not in TH2 cells. Forced expression of GATA3, a factor known to promote the TH2 cell fate, in TH1 cells prevented Runx3 binding to the Il4 silencer. Precisely how GATA3 ‘expels’ Runx complexes from the Il4 silencer gene remains to be investigated.

Encouragingly, as human RUNX3 lies adjacent to a cluster of genes thought to influence asthma susceptibility in humans, these data may hold clinical significance. “The Il4 gene might not be the only immunologically relevant target of Runx complexes. Further studies focusing on the roles of Runx complexes in mice may provide further insight into the molecular pathogenesis of allergic and autoimmune human diseases,” says Taniuchi.
Reference

1. Naoe, Y., Setoguchi, R., Akiyama, K., Muroi, S., Kuroda, M., Hatam, F., Littman, D.R. & Taniuchi, I. Repression of interleukin-4 in T helper type 1 cells by Runx/Cbfβ binding to the Il4 silencer. The Journal of Experimental Medicine 204, 1749–1755 (2007).

Published: 19 Oct 2007

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http://www.rikenresearch.riken.jp/research/324/image_1200.html Figure 1: Spontaneous airway infiltration was observed in mice lacking the CBFβ protein (left) but not in wild-type (right) mice.

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The Journal of Experimental Medicine

Medicine