INFLAMMATION AND INFLAMMATORY BOWEL DISEASE

Activation of signal transducer and activator of transcription (STAT) 1 in human chronic inflammatory bowel disease

S Schreiber¹, P Rosenstiel³, J Hampe¹, S Nikolaus¹, B Groessner², A Schottelius^4,, T Kühbacher⁵, J Hämling¹, U R Fölsch¹, D Seegert¹

¹ 1st Department of Medicine, Christian-Albrechts-University, Schittenhelmstrasse 12, Kiel, Germany
² Hospital for Conserative Dentistry and periodontology, Christian-Albrechts-University, Kiel, Germany
³ Institute for Anatomy, Christian-Albrechts-University, Kiel, Germany
⁴ Charité University Hospital, 4th Medical Department, Humboldt University, Berlin, Germany
⁵ Clinica Media I, Policlinico S Orsola, University of Bologna, Italy

Correspondence to:
Correspondence to:
Dr S Schreiber, 1st Medical Department, Christian-Albrechts-University, Schittenhelmstrasse 12, 24105 Kiel, Germany;
s.schreiber{at}mucosa.de

Background: Increased expression of proinflammatory cytokines, including tumour necrosis factor , interleukin 6, and interferon , as well as activation of proinflammatory signalling molecules such as nuclear factor kappa B, is characteristic of inflammatory bowel disease (IBD).

Aims: To investigate expression and activation of signal transducer and activator of transcription (STAT) 1 in patients with IBD.

Patients: Patients with active IBD (n=42), disease specificity controls (n=8), and normal controls (n=12) were investigated.

Methods: Expression and activation of STAT1 were assessed by western blotting and electrophoretic mobility shift assays in extracts of endoscopic colonic biopsies. Cellular localisation was determined by immunohistochemistry.

Results: Western blots and immunohistochemical staining revealed an increase in STAT1 expression and activation in mucosal samples from ulcerative colitis and to a lesser extend in Crohn's disease patients. High levels of suppressor of cytokine signalling (SOCS)-3 expression, an inhibitor of STAT activation, were observed in Crohn's disease patients and normal controls in western blot experiments whereas no differences were observed for SOCS-1 expression. Phosphorylated (p) STAT1 was mainly detected in monocytic cells and neutrophils in the inflamed mucosa. Induction of remission by systemic glucocorticoids led to a decrease in levels of pSTAT1. In vitro studies indicated a direct effect of steroid treatment on STAT1 activation.

Conclusions: Expression and activation of STAT1 are predominantly heightened in ulcerative colitis and may therefore play an important role in the pathophysiology of colonic inflammation.

Keywords: inflammatory bowel disease; Crohn's disease; ulcerative colitis; signal transducer and activator of transcription

Abbreviations: IBD, inflammatory bowel disease; STAT, signal transducer and activator of transcription; SOCS, suppressor of cytokine signalling; IFN-, interferon ; TH1, TH2, T helper cell types 1 and 2; IL, interleukin; TNF-, tumour necrosis factor ; NFB, nuclear factor kappa B; JAK, Janus kinases; EMSA, electrophoretic mobility shift assay; PBS, phosphate buffered saline; AP-1, activator protein 1; ICAM-1, intercellular adhesion molecule 1

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