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(American Journal of Pathology. 2003;162:1845-1855.)
© 2003 American Society for Investigative Pathology

Constitutive Activation of the Signal Transducer and Activator of Transcription Pathway in Celiac Disease Lesions

Giuseppe Mazzarella^*, Thomas T. MacDonald, Virginia M Salvati, Peter Mulligan, Luigi Pasquale^¶, Rosita Stefanile^*, Paolo Lionetti^||, Salvatore Auricchio, Francesco Pallone^**, Riccardo Troncone and Giovanni Monteleone^**

From the Istituto di Scienze dell’Alimentazione,^* Consiglio Nazionale delle Ricerche, Avellino, Italy; the Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy; Gastroenterologia ed Endoscopia Digestiva,^¶ Azienda Ospedaliera "San Giuseppe Moscati," Avellino, Italy; Dipartimento di Pediatria,|| Universita’ di Firenze, Florence, Italy; the Department of Internal Medicine,^** University Tor Vergata of Rome, Rome, Italy; the Division of Infection, Inflammation, and Repair, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, United Kingdom; and the Department of Paediatric and Adult Gastroenterology, St. Bartholomews and the Royal London School of Medicine and Dentistry, London, United Kingdom

The biological effects of interferon (IFN)- 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- 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- 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.

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