Gene-specific control of inflammation by TLR-induced chromatin modifications

Nature 447: 972-978 (2007)

Speaker : 阮馨怡                           Time : 14:10~15:00, Dec.19, 2007

Commentator : 劉校生 老師                  Place: Room 601

Abstract:

   Toll-like receptors (TLRs) involve in early host defense to infection and inflammatory response.¹ However, the activation of TLRs can be a double-edged sword. Previous studies have shown that immune system needs to maintain a balance between activation and inhibition to avoid over-expressed inflammations; TLR signaling must be tightly regulated. TLRs induce a variety of genes, but not all have potential to lead pathological conditions. Lipopolysaccharide (LPS) tolerance² is a phenomenon when continuous infections taken place, the continuous LPS stimulation through TLR4 signaling leads a transient unresponsive state of macrophage. Thus, authors examined whether genes which TLR induced with different biological functions would be controlled for distinct regulated patterns depending on different requirements. Furthermore, authors represented TLR4-induce genes can be divided into two groups; a first group referred to as class “tolerizable (T)” encoding pro-inflammatory mediator have the potential to cause tissue damage must be transiently inactivated and not re-induced. A second group referred to as class “non-tolerizable (NT)” encoding antimicrobial effectors have no harmful influence but provide continuous protection from infection should remain inducible. They also demonstrated because genes from two groups are induced by the same pathway, both expressions are differentially regulated by gene-specific rather then signal-specific including histone modifications and nucleosome remodelling. The acetylation of histone 4 (H4) and trimethylation of H3 at lysine 4 (H3-K4) were observed in both types of genes in naive macrophages but not in class T genes in tolerant macrophages. In addition, chromatin remodelling was inhibited at the promoters of class T genes in tolerant macrophages, whereas NT promoters were stable and remain inducible. Above these evidences illustrated component-specific regulations as a result of TLR4-induced chromatin modifications to control inflammation over-expression.

Reference:

1. Nathan, C. et al. Points of control in inflammation. Nature 420, 846–852 (2002).

2. West, M. A. & Heagy, W. Endotoxin tolerance: A review. Crit. Care Med. 30, S64–S73 (2002).