Constitutive activation of the signal transducer and activator of transcription pathway in celiac disease lesions

Abstract

The biological effects of interferon (IFN)-gamma rely mainly on the activity of the transcription factor signal transducer and activator of transcription (STAT) 1 and the intracellular levels of suppressor of cytokine signaling (SOCS)-1, a negative regulator that controls the amplitude and duration of STAT-1 activation. IFN-gamma is a key mediator of the immunopathology in celiac disease (CD, gluten-sensitive enteropathy). Thus we have investigated STAT-1 signaling and SOCS-1 expression in this condition. As expected, high local concentrations of IFN-gamma were invariably seen in duodenal biopsies from CD patients in comparison to controls. On the basis of immunohistochemistry, STAT-1 phosphorylation, nuclear localization, and DNA-binding activity, STAT-1 activation was consistently more pronounced in CD compared with controls. Despite samples from CD patients containing abundant SOCS-1 mRNA, SOCS-1 protein was expressed at the same level in CD patients and controls. In explant cultures of CD biopsies, gliadin induced the activation of STAT-1 but not SOCS-1. Furthermore, inhibition of STAT-1 prevented the gliadin-mediated induction of ICAM-1 and B7-2. These data suggest that persistent STAT-1 activation can contribute to maintaining and expanding the local inflammatory response in CD.