Yin and yang interplay of IFN-gamma in inflammation and autoimmune disease

Abstract

IFN-gamma has long been recognized as a signature proinflammatory cytokine that plays a central role in inflammation and autoimmune disease. There is now emerging evidence indicating that IFN-gamma possesses unexpected properties as a master regulator of immune responses and inflammation. In this issue of the JCI, Guillonneau et al. show that indefinite allograft survival induced by CD40Ig treatment is mediated by CD8(+)CD45RC(low) T cells through the production of IFN-gamma (see the related article beginning on page 1096), supporting the emerging view that IFN-gamma is critical in the self-regulation of inflammation. These contradictory roles of IFN-gamma, perhaps best understood by the principle of yin and yang, represent one of nature's paradoxes, whereby the same cytokine functions as an inducer as well as a regulator for inflammation. Understanding this complex process of IFN-gamma signaling is essential, as it has therapeutic implications.

Figure 1. The paradoxical roles and interplay of IFN-γ in inflammation and autoimmune disease.

These roles are best illustrated in the familiar diagram of yin and yang, the “Great Ultimate” [T’ai-chi] diagram. When an inflammatory process (yang) is initiated, IFN-γ is produced to promote inflammation through multiple genes of the immune system (some are indicated). As IFN-γ reaches its peak level (the “hot” point), inflammation intensifies (enlargement of yang area) and compresses its opposite. The dominant signal of IFN-γ then flows into the opposite area (yin) and activates a regulatory process through various genes and pathways to reach the “cool” point, resulting in shift of the dividing line toward the reduction of inflammation (enlargement of yin area, mutually compressing its opposite). CIITA, MHC class II–specific transactivator; IL-18BP, IL-18 binding protein; NKG2DL, NK group 2D ligand; TRAIL, TNF-related apoptosis–inducing ligand.