Dysregulation of IFN-γ Signaling Pathways in the Absence of TGF-β1
- 15 November 2002
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 169 (10), 5941-5947
- https://doi.org/10.4049/jimmunol.169.10.5941
Abstract
Deficiency of TGF-beta1 is associated with immune dysregulation and autoimmunity as exemplified by the multifocal inflammatory lesions and early demise of the TGF-beta1 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 Stat1alpha and IFN-regulatory factor-1 (IRF-1). The coincident up-regulation of IFN-gamma, an iNOS inducer, and iNOS, before the appearance of inflammatory lesions, suggests that failed regulation of the IFN-gamma signaling pathway may underlie the immunological disorder in TGF-beta1 null mice. In fact, IFN-gamma-driven transcription factors IRF-1 and Stat1alpha, both of which act as transcriptional activators of iNOS, were elevated in the null mice. Treatment of mice with a polyclonal anti-IFN-gamma Ab reduced expression and activity not only of transcription factors Stat1alpha and IRF-1 but also of iNOS. Furthermore, anti-IFN-gamma treatment delayed the cachexia normally seen in TGF-beta1 null mice and increased their longevity. The global nature of immune dysregulation in TGF-beta1 null mice documents TGF-beta1 as an essential immunoregulatory molecule.Keywords
This publication has 37 references indexed in Scilit:
- Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator?Immunology Today, 1998
- Induction of interferons and interferon-induced genesBiotherapy, 1996
- Targeted Disruption of the Stat1 Gene in Mice Reveals Unexpected Physiologic Specificity in the JAK–STAT Signaling PathwayCell, 1996
- Role of interferon regulatory factor 1 in induction of nitric oxide synthase.The Journal of Experimental Medicine, 1994
- N‐Monomethyl arginine, an inhibitor of nitric oxide synthase, suppresses the development of adjuvant arthritis in ratsArthritis & Rheumatism, 1994
- Requirement for Transcription Factor IRF-1 in NO Synthase Induction in MacrophagesScience, 1994
- The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine.The Journal of Experimental Medicine, 1994
- Suppression of arthritis by an inhibitor of nitric oxide synthase.The Journal of Experimental Medicine, 1993
- Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta.The Journal of Experimental Medicine, 1993
- Role of nitric oxide in antagonistic effects of transforming growth factor-beta and interleukin-1 beta on the beating rate of cultured cardiac myocytesMolecular Endocrinology, 1992