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IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis
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 ind...
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| Published in: | The Journal of clinical investigation 2010-06, Vol.120 (6), p.2131-2143 |
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| creator | Malamut, Georgia El Machhour, Raja Montcuquet, Nicolas Martin-Lannerée, Séverine Dusanter-Fourt, Isabelle Verkarre, Virginie Mention, Jean-Jacques Rahmi, Gabriel Kiyono, Hiroshi Butz, Eric A Brousse, Nicole Cellier, Christophe Cerf-Bensussan, Nadine Meresse, Bertrand |
| description | 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. |
| doi_str_mv | 10.1172/JCI41344 |
| format | article |
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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.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI41344</identifier><identifier>PMID: 20440074</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>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</subject><ispartof>The Journal of clinical investigation, 2010-06, Vol.120 (6), p.2131-2143</ispartof><rights>COPYRIGHT 2010 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Jun 2010</rights><rights>Copyright © 2010, American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c673t-22363d0832acd221c86eeda613f21882453f4f848ed7ac9c0c3024fc5b4a32f83</citedby><cites>FETCH-LOGICAL-c673t-22363d0832acd221c86eeda613f21882453f4f848ed7ac9c0c3024fc5b4a32f83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877946/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877946/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,730,783,787,888,27937,27938,53805,53807</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20440074$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Malamut, Georgia</creatorcontrib><creatorcontrib>El Machhour, Raja</creatorcontrib><creatorcontrib>Montcuquet, Nicolas</creatorcontrib><creatorcontrib>Martin-Lannerée, Séverine</creatorcontrib><creatorcontrib>Dusanter-Fourt, Isabelle</creatorcontrib><creatorcontrib>Verkarre, Virginie</creatorcontrib><creatorcontrib>Mention, Jean-Jacques</creatorcontrib><creatorcontrib>Rahmi, Gabriel</creatorcontrib><creatorcontrib>Kiyono, Hiroshi</creatorcontrib><creatorcontrib>Butz, Eric A</creatorcontrib><creatorcontrib>Brousse, Nicole</creatorcontrib><creatorcontrib>Cellier, Christophe</creatorcontrib><creatorcontrib>Cerf-Bensussan, Nadine</creatorcontrib><creatorcontrib>Meresse, Bertrand</creatorcontrib><title>IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>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.</description><subject>Adult</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - immunology</subject><subject>Biomedical research</subject><subject>Care and treatment</subject><subject>Celiac disease</subject><subject>Celiac Disease - complications</subject><subject>Celiac Disease - immunology</subject><subject>Celiac Disease - metabolism</subject><subject>Cytokines</subject><subject>Cytokines - immunology</subject><subject>Cytokines - metabolism</subject><subject>Cytokines - pharmacology</subject><subject>Development and progression</subject><subject>Enterocytes - immunology</subject><subject>Enterocytes - metabolism</subject><subject>Gluten</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Inflammation - complications</subject><subject>Inflammation - immunology</subject><subject>Inflammation - metabolism</subject><subject>Interleukin-15</subject><subject>Interleukin-15 - immunology</subject><subject>Interleukin-15 - metabolism</subject><subject>Interleukin-15 - pharmacology</subject><subject>Intestine, Small - immunology</subject><subject>Intestine, Small - metabolism</subject><subject>Intestines - immunology</subject><subject>Intestines - metabolism</subject><subject>Janus Kinase 3 - immunology</subject><subject>Janus Kinase 3 - metabolism</subject><subject>Leukemia - complications</subject><subject>Leukemia - immunology</subject><subject>Leukemia - metabolism</subject><subject>Lymphocytes</subject><subject>Lymphocytes - immunology</subject><subject>Lymphocytes - metabolism</subject><subject>Lymphoma</subject><subject>Medical prognosis</subject><subject>Non-Hodgkin's lymphomas</subject><subject>Phosphorylation</subject><subject>Properties</subject><subject>Protein Binding - immunology</subject><subject>Signal Transduction - 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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.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>20440074</pmid><doi>10.1172/JCI41344</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-9738 |
| ispartof | The Journal of clinical investigation, 2010-06, Vol.120 (6), p.2131-2143 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2877946 |
| source | PubMed (Medline); Free E-Journal (出版社公開部分のみ） |
| subjects | 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 |
| title | IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-11-11T02%3A47%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=IL-15%20triggers%20an%20antiapoptotic%20pathway%20in%20human%20intraepithelial%20lymphocytes%20that%20is%20a%20potential%20new%20target%20in%20celiac%20disease-associated%20inflammation%20and%20lymphomagenesis&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Malamut,%20Georgia&rft.date=2010-06-01&rft.volume=120&rft.issue=6&rft.spage=2131&rft.epage=2143&rft.pages=2131-2143&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI41344&rft_dat=%3Cgale_pubme%3EA241944794%3C/gale_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c673t-22363d0832acd221c86eeda613f21882453f4f848ed7ac9c0c3024fc5b4a32f83%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=367408514&rft_id=info:pmid/20440074&rft_galeid=A241944794&rfr_iscdi=true |