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

Abstract

The biological effects of interferon (IFN)-The major signal transduction pathway initiated by interferon (IFN)-␥ has been elucidated by a series of elegant biochemical and genetic studies. Binding of IFN-␥ to its receptor induces dimerization of the receptor chains, bringing together JAK kinases 1 and 2 that are activated by transphosphorylation. Activated JAK-1 and -2 then phosphorylate tyrosine residues within the cytoplasmic domains of the receptor subunits, which act as a docking site for a latent cytoplasmic protein, termed signal transducer and activator of transcription 1 (STAT-1). Phosphorylation of a C-terminal tyrosine (Y701) in STAT-1 facilitates interaction with the SH2 domain of a second STAT-1 molecule, mediating dimerization. STAT-1 can also be phosphorylated on a single serine residue (Ser-727) at the carboxy end of the molecule.

The effect of gluten-free diet on Th1–Th2–Th3-associated intestinal immune responses in celiac disease

“…Although GFD for one year did down regulate these markers the expression of STAT1 and IRF1 genes were still elevated in treated children with CD compared to reference children. The findings in our study are in agreement with previous reports of the increased intestinal IFN-γ and STAT1 expression in untreated CD both at RNA and protein level [7,9,[18][19][20][21][22]. Further, IRF1 which is involved in IFN-γ [23,24] and TNF mediated responses [25] via regulation of the induction of NO/iNOS in macrophages [24,26] has previously been reported to be elevated at RNA and protein level in biopsies from untreated CD children [18].…”

“…The intestinal immune cells in CD produce IFN-γ and TNF-α [4,7,8], which are believed to be involved in the pathogenesis. The janus kinase -signal transducer and activator of transcription (JAK-STAT) pathway, which mediates a Th1 (IFN-γ) response through activation of STAT proteins, has been reported to be of importance in the CD pathogenesis [7,9]. Apart from IFN-γ, also other cytokines as IFN-α/β, interleukin (IL) 6, TNF-α and transforming growth factor (TGF)- that can activate or cross-talk with the JAK-STAT signalling pathway are suggested to be of importance in CD [10,11].…”

Gliadin Regulates the NK-Dendritic Cell Cross-Talk by HLA-E Surface Stabilization

“…Tissue sections were prepared as described previously (46). Anti-HLA-E mAb (MEM-02; 4 g/ml) was added at 4°C overnight.…”

Adaptive and innate immune responses in celiac disease

“…␥-Interferon-dependent signaling pathways have been found to be enhanced in CD. Signal transducer and activator of transcription 1 (STAT1) [17] and interferon regulating factor 1 (IRF1) have both been found more expressed in untreated CD and in treated CD mucosa in vitro challenged with gliadin [18]. IL-10 is also upregulated, not to same extent as ␥-interferon, the IL-10/␥-interferon ratio being significantly lower in untreated CD [16].…”