Dysregulation of IFN-γ Signaling Pathways in the Absence of TGF-β1

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Abstract
Deficiency of TGF-β1 is associated with immune dysregulation and autoimmunity as exemplified by the multifocal inflammatory lesions and early demise of the TGF-β1 null mice. Elevated NO metabolites (nitrite and nitrate) in the plasma of these mice suggest a participatory role of NO in the pathogenic inflammatory response. To determine the mechanism for this dysregulation, we examined upstream elements that could contribute to the overexpression of NO, including inducible NO synthase (iNOS) and transcription factors Stat1α and IFN-regulatory factor-1 (IRF-1). The coincident up-regulation of IFN-γ, an iNOS inducer, and iNOS, before the appearance of inflammatory lesions, suggests that failed regulation of the IFN-γ signaling pathway may underlie the immunological disorder in TGF-β1 null mice. In fact, IFN-γ-driven transcription factors IRF-1 and Stat1α, both of which act as transcriptional activators of iNOS, were elevated in the null mice. Treatment of mice with a polyclonal anti-IFN-γ Ab reduced expression and activity not only of transcription factors Stat1α and IRF-1 but also of iNOS. Furthermore, anti-IFN-γ treatment delayed the cachexia normally seen in TGF-β1 null mice and increased their longevity. The global nature of immune dysregulation in TGF-β1 null mice documents TGF-β1 as an essential immunoregulatory molecule.