Trends in Immunology
ReviewHow interferon-γ keeps autoimmune diseases in check
Introduction
In many reports and reviews, interferon γ (IFN-γ) is treated as a proinflammatory cytokine. Historically, it owes this attribute first to its strong macrophage-activating potential. Although IFN-γ–activated macrophages are crucial for host defense against intracellular pathogens, they are also prominent players in inflammatory tissue changes that accompany infection. Furthermore, the concept of IFN-γ being proinflammatory was strengthened by the Th1-Th2 paradigm that associates IFN-γ with Th1-driven immune responses, not only in the effector phase but also as one of the autocrine factors favouring Th1-directed differentiation.
Whereas these views were derived mainly from in vitro observations at the cellular level, the question of how, in reality, endogenous IFN-γ affects inflammation has been addressed using various in vivo animal model systems, including ones of Th1-driven autoimmune disease (Table 1). The expected overall proinflammatory and disease-enforcing role became evident in only some models, with strong evidence for protection against inflammation and disease manifestations in others. These observations question the classic proinflammatory role of IFN-γ but also the Th1-Th2 paradigm as a basis for explaining the regulation of autoimmune diseases. One model, collagen-induced arthritis (CIA) in mice, is exceptional in that it can be tuned such that IFN-γ ablation either enhances or inhibits disease. Here, we will discuss this model as a viewpoint from which to weigh the pro- against anti-inflammatory properties of IFN-γ. Next we will consider evidence from other models in this context.
Section snippets
CIA in mice as a study model for the inflammation-regulatory role of IFN-γ
‘Classical’ murine CIA is induced by immunization of susceptible mice with collagen type II in complete Freund's adjuvant (CFA). Ablation of IFN-γ using gene knockout (KO) technology or treatment with neutralizing anti-IFN-γ antibody results in aggravation of the joint lesions, indicating that, under these conditions, endogenous IFN-γ inhibits one or more crucially important inflammatory pathway(s) 1, 2. The joint lesions are considered manifestations of autoimmunity, involving both cellular
Comparison with autoimmune models other than CIA
A net protective effect of endogenous IFN-γ occurs in disease models other than CIA, namely EAE, EAU, autoimmune nephritis, and myocarditis 41, 42, 43, 44, 45, 46, 47. These models share with CIA the use of CFA as a critical component of immunization protocols, suggesting that enhanced myelopoiesis might constitute an important factor in their pathogenesis and in modulation by IFN-γ. Thus far, direct experimental evidence to that effect is not available. Nevertheless, several studies have
Concluding remarks
On the basis of its most prominent biological activities, such as macrophage activation and regulatory involvement in Th1-type responses, IFN-γ is traditionally heralded as a proinflammatory cytokine. Despite early in vivo evidence to the opposite (Table 1), most notably aggravation of EAE in mice in which IFN-γ signaling was interrupted, this oversimplified view has long persisted in the IFN-γ literature. As reviewed here, accumulating data have revealed the existence of diverse mechanisms by
Acknowledgements
This study was supported by the Fund for Scientific Research-Flanders (FWO-Vlaanderen) and the Geconcerteerde OnderzoeksActies (GOA). H.K. received a fellowship from the FWO Vlaanderen and is currently a postdoctoral fellow of the K.U. Leuven.
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