Type I IFN and TNFα cross-regulation in immune-mediated inflammatory disease: basic concepts and clinical relevance

Abstract

A cross-regulation between type I IFN and TNFα has been proposed recently, where both cytokines are hypothesized to counteract each other. According to this model, different autoimmune diseases can be viewed as disequilibrium between both cytokines. As this model may have important clinical implications, the present review summarizes and discusses the currently available clinical evidence arguing for or against the proposed cross-regulation between TNFα and type I IFN. In addition, we review how this cross-regulation works at the cellular and molecular levels. Finally, we discuss the clinical relevance of this proposed cross-regulation for biological therapies such as type I IFN or anti-TNFα treatment.

Figure 1

Cross-regulation between type I IFN and TNFα. (a) The original hypothesis proposes that both cytokines can be regarded as opposite vectors. Whereas the sum of both vectors normally yields an equilibrium point allowing protective immunity, disturbance of this balance beyond a certain threshold may contribute to a pathological state promoting autoimmunity, allergy, or inflammation. A shift towards the TNFα arm may create a permissive environment for TNF-mediated autoimmunity in rheumatoid arthritis (RA). In contrast, when the type I IFN arm prevails, IFN-driven autoimmunity as observed in systemic lupus erythematosus (SLE) may occur. (b) An alternative hypothesis: in homeostatic conditions, type I IFN and TNFα are influencing each other's levels but this balance is lost in a pathological condition. (c) An alternative hypothesis: type I IFN plays an important role in the initiation of autoimmunity, while the role of TNFα increases during the secondary inflammatory phase.