The Journal of clinical investigation, 2010-06, Vol.120 (6), p.2131-2143
2010
Details
- Autor(en) / Beteiligte
- Titel
- IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis
- Ist Teil von
- The Journal of clinical investigation, 2010-06, Vol.120 (6), p.2131-2143
- Ort / Verlag
- United States: American Society for Clinical Investigation
- Erscheinungsjahr
- 2010
- Link zum Volltext
- Quelle
- EZB Free E-Journals
- Beschreibungen/Notizen
- Enteropathy-associated T cell lymphoma is a severe complication of celiac disease (CD). One mechanism suggested to underlie its development is chronic exposure of intraepithelial lymphocytes (IELs) to potent antiapoptotic signals initiated by IL-15, a cytokine overexpressed in the enterocytes of individuals with CD. However, the signaling pathway by which IL-15 transmits these antiapoptotic signals has not been firmly established. Here we show that the survival signals delivered by IL-15 to freshly isolated human IELs and to human IEL cell lines derived from CD patients with type II refractory CD (RCDII) - a clinicopathological entity considered an intermediary step between CD and enteropathy-associated T cell lymphoma - depend on the antiapoptotic factors Bcl-2 and/or Bcl-xL. The signals also required IL-15Rbeta, Jak3, and STAT5, but were independent of PI3K, ERK, and STAT3. Consistent with these data, IELs from patients with active CD and RCDII contained increased amounts of Bcl-xL, phospho-Jak3, and phospho-STAT5. Furthermore, incubation of patient duodenal biopsies with a fully humanized human IL-15-specific Ab effectively blocked Jak3 and STAT5 phosphorylation. In addition, treatment with this Ab induced IEL apoptosis and wiped out the massive IEL accumulation in mice overexpressing human IL-15 in their gut epithelium. Together, our results delineate the IL-15-driven survival pathway in human IELs and demonstrate that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9738eISSN: 1558-8238DOI: 10.1172/JCI41344Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2877946
- Format
- –
- Schlagworte
- Adult, Apoptosis, Apoptosis - drug effects, Apoptosis - immunology, Biomedical research, Care and treatment, Celiac disease, Celiac Disease - complications, Celiac Disease - immunology, Celiac Disease - metabolism, Cytokines, Cytokines - immunology, Cytokines - metabolism, Cytokines - pharmacology, Development and progression, Enterocytes - immunology, Enterocytes - metabolism, Gluten, Health aspects, Humans, Inflammation, Inflammation - complications, Inflammation - immunology, Inflammation - metabolism, Interleukin-15, Interleukin-15 - immunology, Interleukin-15 - metabolism, Interleukin-15 - pharmacology, Intestine, Small - immunology, Intestine, Small - metabolism, Intestines - immunology, Intestines - metabolism, Janus Kinase 3 - immunology, Janus Kinase 3 - metabolism, Leukemia - complications, Leukemia - immunology, Leukemia - metabolism, Lymphocytes, Lymphocytes - immunology, Lymphocytes - metabolism, Lymphoma, Medical prognosis, Non-Hodgkin's lymphomas, Phosphorylation, Properties, Protein Binding - immunology, Signal Transduction - drug effects, Signal Transduction - immunology, STAT3 Transcription Factor - immunology, STAT3 Transcription Factor - metabolism, STAT3 Transcription Factor - pharmacology, T cell receptors, T cells