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PMID: 19563763 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut.

Cell ·Vol. 137 ·No. 7 ·2009-06-26 ·Pages 1343-55

Jiang H, Patel PH, Kohlmaier A, Grenley MO, McEwen DG, Edgar BA

Abstract

Cells in intestinal epithelia turn over rapidly due to damage from digestion and toxins produced by the enteric microbiota. Gut homeostasis is maintained by intestinal stem cells (ISCs) that divide to replenish the intestinal epithelium, but little is known about how ISC division and differentiation are coordinated with epithelial cell loss. We show here that when enterocytes (ECs) in the Drosophila midgut are subjected to apoptosis, enteric infection, or JNK-mediated stress signaling, they produce cytokines (Upd, Upd2, and Upd3) that activate Jak/Stat signaling in ISCs, promoting their rapid division. Upd/Jak/Stat activity also promotes progenitor cell differentiation, in part by stimulating Delta/Notch signaling, and is required for differentiation in both normal and regenerating midguts. Hence, cytokine-mediated feedback enables stem cells to replace spent progeny as they are lost, thereby establishing gut homeostasis.

MeSH Terms
Animals Apoptosis Cytokines/metabolism Drosophila/cytology,immunology,metabolism,microbiology Drosophila Proteins/metabolism Enterocytes/cytology,metabolism Homeostasis Intestines/cytology,microbiology,physiology Janus Kinases/metabolism Regeneration STAT Transcription Factors/metabolism Signal Transduction Stem Cells/cytology,metabolism Transcription Factors/metabolism
Chemicals
Cytokines Drosophila Proteins STAT Transcription Factors Transcription Factors Janus Kinases hop protein, Drosophila
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Jiang Huaqi
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Patel Parthive H
Kohlmaier Alexander
Grenley Marc O
McEwen Donald G
Edgar Bruce A
References (44)
44 references, click to expand
  1. An antioxidant system required for host protection against gut infection in Drosophila.
    Dev Cell. 2005 Jan;8(1):125-32 PMID: 15621536
  2. Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells.
    Nature. 2008 Oct 23;455(7216):1119-23 PMID: 18806781
  3. Puckered, a Drosophila MAPK phosphatase, ensures cell viability by antagonizing JNK-induced apoptosis.
    Development. 2005 Sep;132(17):3935-46 PMID: 16079158
  4. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut.
    Cell Stem Cell. 2008 Oct 9;3(4):442-55 PMID: 18940735
  5. Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling.
    Science. 2007 Feb 16;315(5814):988-92 PMID: 17303754
  6. The role of stem cells in midgut growth and regeneration.
    In Vitro Cell Dev Biol Anim. 2001 Jun;37(6):338-42 PMID: 11515964
  7. Innate immune homeostasis by the homeobox gene caudal and commensal-gut mutualism in Drosophila.
    Science. 2008 Feb 8;319(5864):777-82 PMID: 18218863
  8. Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways.
    Dev Cell. 2004 Oct;7(4):491-501 PMID: 15469838
  9. Drosophila host defense after oral infection by an entomopathogenic Pseudomonas species.
    Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11414-9 PMID: 16061818
  10. p38 mitogen-activated protein kinase can be involved in transforming growth factor beta superfamily signal transduction in Drosophila wing morphogenesis.
    Mol Cell Biol. 1999 Mar;19(3):2322-9 PMID: 10022918
  11. Signaling role of hemocytes in Drosophila JAK/STAT-dependent response to septic injury.
    Dev Cell. 2003 Sep;5(3):441-50 PMID: 12967563
  12. Colorectal cancer risk in Crohn's disease.
    World J Gastroenterol. 2008 Mar 28;14(12):1810-1 PMID: 18350616
  13. GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo.
    Gene Expr Patterns. 2007 Jan;7(3):323-31 PMID: 17008134
  14. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2.
    Nat Rev Cancer. 2001 Oct;1(1):11-21 PMID: 11900248
  15. Wnt signaling in the intestinal epithelium: from endoderm to cancer.
    Genes Dev. 2005 Apr 15;19(8):877-90 PMID: 15833914
  16. Mechanism of cyclooxygenase-2 upregulation in late preconditioning.
    J Mol Cell Cardiol. 2003 May;35(5):525-37 PMID: 12738234
  17. puckered encodes a phosphatase that mediates a feedback loop regulating JNK activity during dorsal closure in Drosophila.
    Genes Dev. 1998 Feb 15;12(4):557-70 PMID: 9472024
  18. IL-6 signaling promotes tumor growth in colorectal cancer.
    Cell Cycle. 2005 Feb;4(2):217-20 PMID: 15655344
  19. Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation.
    Gastroenterology. 2008 Oct;135(4):1311-21 PMID: 18700144
  20. NSAIDs and cancer prevention: targets downstream of COX-2.
    Annu Rev Med. 2007;58:239-52 PMID: 17100552
  21. A cytokine-mediated link between innate immunity, inflammation, and cancer.
    J Clin Invest. 2007 May;117(5):1175-83 PMID: 17476347
  22. Regulatory roles of JNK in programmed cell death.
    J Biochem. 2004 Jul;136(1):1-6 PMID: 15269233
  23. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control.
    Nat Rev Genet. 2006 May;7(5):349-59 PMID: 16619050
  24. Localized Notch signal acts through eyg and upd to promote global growth in Drosophila eye.
    Development. 2004 Aug;131(16):3839-47 PMID: 15253935
  25. Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention.
    Biochem Pharmacol. 2004 Sep 15;68(6):1089-100 PMID: 15313405
  26. Krüppel-like factor 5 mediates transmissible murine colonic hyperplasia caused by Citrobacter rodentium infection.
    Gastroenterology. 2008 Apr;134(4):1007-16 PMID: 18395082
  27. The molecular cloning and characterization of Drosophila melanogaster myosin-IA and myosin-IB.
    J Mol Biol. 1994 Jun 10;239(3):347-56 PMID: 8201616
  28. Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation.
    Cell Host Microbe. 2009 Feb 19;5(2):200-11 PMID: 19218090
  29. A model Notch response element detects Suppressor of Hairless-dependent molecular switch.
    Curr Biol. 2001 Jan 9;11(1):60-4 PMID: 11166182
  30. The IkappaB kinase - a bridge between inflammation and cancer.
    Cell Res. 2008 Mar;18(3):334-42 PMID: 18301380
  31. Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon.
    Oncogene. 2007 Jul 19;26(33):4833-41 PMID: 17297444
  32. The adult Drosophila posterior midgut is maintained by pluripotent stem cells.
    Nature. 2006 Jan 26;439(7075):470-4 PMID: 16340960
  33. Interleukin-6 stimulates clonogenic growth of primary and metastatic human colon carcinoma cells.
    Cancer Lett. 2000 Apr 3;151(1):31-8 PMID: 10766420
  34. Spatiotemporal gene expression targeting with the TARGET and gene-switch systems in Drosophila.
    Sci STKE. 2004 Feb 12;2004(220):pl6 PMID: 14970377
  35. EGFR signaling regulates the proliferation of Drosophila adult midgut progenitors.
    Development. 2009 Feb;136(3):483-93 PMID: 19141677
  36. Inflammation, HCC and sex: IL-6 in the centre of the triangle.
    J Hepatol. 2008 Feb;48(2):380-1 PMID: 18093689
  37. Evidence that stem cells reside in the adult Drosophila midgut epithelium.
    Nature. 2006 Jan 26;439(7075):475-9 PMID: 16340959
  38. A novel functional activator of the Drosophila JAK/STAT pathway, unpaired2, is revealed by an in vivo reporter of pathway activation.
    Mech Dev. 2005 Jul;122(7-8):939-48 PMID: 15925495
  39. Tissue damage-induced intestinal stem cell division in Drosophila.
    Cell Stem Cell. 2009 Jan 9;4(1):49-61 PMID: 19128792
  40. Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors.
    J Clin Pathol. 2005 Aug;58(8):833-8 PMID: 16049285
  41. Drosophila Pxt: a cyclooxygenase-like facilitator of follicle maturation.
    Development. 2008 Mar;135(5):839-47 PMID: 18216169
  42. Circulating interleukin-6 induces fever through a STAT3-linked activation of COX-2 in the brain.
    Am J Physiol Regul Integr Comp Physiol. 2006 Nov;291(5):R1316-26 PMID: 16809483
  43. Control of life, death, and differentiation in cultured midgut cells of the lepidopteran, Heliothis virescens.
    In Vitro Cell Dev Biol Anim. 2001 Jun;37(6):348-52 PMID: 11515966
  44. Signaling pathways in intestinal development and cancer.
    Annu Rev Cell Dev Biol. 2004;20:695-723 PMID: 15473857
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2009.05.014
Published
2009-06-26
Pages
1343-55
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2753793
Subset
IM
Grants
NIGMS NIH HHS · R01 GM051186 · United States
NIGMS NIH HHS · R01 GM051186-14A1 · United States
NIGMS NIH HHS · R01 GM051186-15 · United States
NIGMS NIH HHS · R01 GM51186 · United States
Corrections
CommentIn
PMID: 19563751
External Links
PubMed source DOI: 10.1016/j.cell.2009.05.014 PMC Full Text View journal details
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