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Signaling Pathways in the Absence of TGF-
1
Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892
Deficiency of TGF-
1 is associated with immune dysregulation and
autoimmunity as exemplified by the multifocal inflammatory lesions and
early demise of the TGF-1 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 Stat1
and
IFN-regulatory factor-1 (IRF-1). The coincident up-regulation of
IFN-
, an iNOS inducer, and iNOS, before the appearance of
inflammatory lesions, suggests that failed regulation of the IFN-
signaling pathway may underlie the immunological disorder in TGF-1
null mice. In fact, IFN--driven transcription factors IRF-1 and
Stat1, both of which act as transcriptional activators of iNOS, were
elevated in the null mice. Treatment of mice with a polyclonal
anti-IFN- Ab reduced expression and activity not only of
transcription factors Stat1 and IRF-1 but also of iNOS. Furthermore,
anti-IFN- treatment delayed the cachexia normally seen in
TGF-1 null mice and increased their longevity. The global nature of
immune dysregulation in TGF-1 null mice documents TGF-1 as an
essential immunoregulatory molecule.
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