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

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.

Aberrant Toll Receptor Expression and Endotoxin Hypersensitivity in Mice Lacking a Functional TGF-β1 Signaling Pathway

“…Also contributing to the milieu of inflammatory mediators, iNOS gene expression was elevated, most dramatically in the hearts of the null mice (Fig. 1C) and was reflected in the circulation by increased levels of nitrite and nitrate, decomposition products of NO, in the plasma (7,8). This dysregulation of proinflammatory cytokine and iNOS gene expression in the absence of TGF-␤1 likely drives the pathology observed in the TGF-␤1 null mice.…”

“…Because of the rapid and striking induction of iNOS in the TGF-␤1 null mice in response to LPS, we next looked for evidence of NO in the circulation, characteristic of inflammatory disease (8). Plasma levels of NO in the LPS-injected mice were measured by a NO analyzer.…”

“…The shared, albeit less severe, pathophysiology in mice lacking a functional TGF-␤R (TGF-␤RII dominant negative) (3)(4)(5) or the TGF-␤ transcription factor Smad3 (6) highlights the essential function of TGF-␤. In the TGF-␤1 null mouse, the infiltration of mononuclear cells into vital organs is accompanied by the overexpression of IFN-␥ and inducible NO synthase (iNOS) 2 and the resulting toxic levels of NO contribute to the lethal phenotype of the TGF-␤1 null mice (7,8). Key to the regulation of inflammation and the expression of iNOS and other proinflammatory mediators is the activation of NF-B, a critical transcription factor involved in the activation of a large number of target genes (9).…”

TGF-β1 Inhibits T-bet Induction by IFN-γ in Murine CD4+ T Cells through the Protein Tyrosine Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-1

“…IFN-␥ is required for disease, because BALB/c-TGF-␤1 Ϫ/Ϫ IFN-␥ Ϫ/Ϫ double-knockout mice are protected (7,11). Tissues isolated from TGF-␤1 Ϫ/Ϫ mice show chronic activation of the IFN-␥ signaling pathway (12), indicating that TGF-␤1 has an important role in vivo in inhibiting IFN-␥ signaling. Unraveling the mechanisms underlying the antagonistic relationship between TGF-␤1 and IFN-␥ is important for understanding the delicate balance between tolerance and autoimmunity.…”

TGF-β1 inhibition of IFN-γ-induced signaling and Th1 gene expression in CD4+ T cells is Smad3 independent but MAP kinase dependent

“…Target organs in TGF-β1 −/− mice accumulate activated Th1 cells (Gorham et al, 2001), and end organ damage is dependent both upon the CD4 + T cell subset (Letterio et al, 1996;Rudner et al, 2003), and the Th1 cytokine IFN-γ (Gorham et al, 2001). Tissues from TGF-β1 −/− mice show evidence of constitutive IFN-γ signaling (McCartney-Francis and Wahl, 2002), indicating that TGF-β1 normally acts to inhibit IFN-γ signaling. IFN-γ and TGF-β1 are antagonistic cytokines that regulate Th1 development in opposite directions.…”