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Endoplasmic Reticulum Stress in Health and Disease pp 281–298Cite as

ER Stress in Intestinal Inflammatory Disease

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Abstract

Earlier chapters have discussed the details of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). In this chapter, we will focus attention on intestinal epithelial cells (IEC) which are unique as they are highly secretory cells that are exposed to a great number of ER stress inducers such as bacteria, xenobiotics, toxins, and hypoxia amongst many other factors (Kaser and Blumberg, Mucosal Immunol 3:11–16, 2010). At the same time, IECs are responsible for absorption of nutrients to sustain the host and actively participate in regulation of immune responses in the gut (Artis, Nat Rev Immunol 8:411–420, 2008). Thus the intestinal epithelium has evolved to possess mechanisms that allow for quick but precise resolution of the ER stress back to the levels required for homeostatic functions. Various defects in the UPR pathways from expression of proteins that easily misfold, through defects in the folding apparatus of the ER to abnormalities in the elements directly associated with the UPR within the ER itself may lead to the intestinal inflammation (Fig. 1) which is associated with diseases such as inflammatory bowel disease (IBD) (Kaser and Blumberg, Mucosal Immunol 3:11–16, 2010; Kaser et al., Annu Rev Immunol 28:573–621, 2010). This chapter will review these concepts in light of fundamental biology of the UPR as discussed in the previous chapters of this book.

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Abbreviations

AGR2:

Anterior gradient 2

ATF6:

Activating transcription factor 6

ATG16L1:

Autophagy related protein16-like 1

ATG7:

Autophagy related protein 7

ATP:

Adenosine triphosphate

b2m:

b2-microglobulin

Bcl2:

B-cell leukemia/lymphoma 2

BiP:

Immunoglobulin heavy chain-binding protein

C/EBP:

CAATT/enhancer binding protein

CaMKKb:

Ca2 + /calmodulin-dependent protein kinase kinase-β

cAMP:

Cyclic adenosine monophosphate

CD:

Crohn’s disease

CHOP:

C/EBP homologous protein

DAP:

Death-associated protein

DSS:

Dextran sodium sulfate

eIF2α:

Eukaryotic initiation factor 2 α

ENU:

N-ethyl-N-nitrosourea

ER:

Endoplasmic reticulum

Ern2:

Endoplasmic reticulum to nucleus signaling 2

GADD34:

Growth arrest and DNA-damage-inducible 34

GCN2:

General control non-depressible 2

GRP78:

Glucose-regulated protein, 78 kDa

Haspa5:

Heat shock 70 kDa protein 5

HLA-B27:

Human leukocyte antigen B27

HRI:

Heme regulated inhibitor

I/R:

Ischemia reperfusion

IBD:

Inflammatory bowel disease

IEC:

Intestinal epithelial cell

IL:

Interleukin

IRE1:

Inositol-requiring enzyme 1

IRF4:

Interferon regulatory factor 4

IRGM:

Immunity-related GTPase family M protein

JNK:

c-Jun N-terminal kinase

LRKK2:

Leucine-rich repeat kinase 2

Mbtps1:

Membrane-bound transcription factor peptidase, site 1

MMP7:

Matrix metallopeptidase 7

mTOR:

Mechanistic target of rapamycin

MUC2:

Mucin 2

NF-kB:

Nuclear factor kB

NOD2:

Nucleotide oligomerization domain gene 2

ORMDL3:

Orosomucoid 1-like protein 3

PDI:

Protein disulfide isomerase

PERK:

Pancreatic EIF2-a kinase

PI3K:

Phosphatidylinositol-3-kinase

PKC-t:

Protein kinase C t

PKR:

Double stranded RNA activated protein kinase

PolyQ72:

Polyglutamine 72

S1P:

Peptidase site 1 protease

SOD1:

Superoxide dismutase 1

SREBPs:

Sterol regulatory element-binding proteins

Th17:

T helper 17

TLR:

Toll like receptor

TNF:

Tumor necrosis factor

TRAF2:

TNF receptor-associated factor 2

UC:

Ulcerative colitis

ULK1:

unc-51-like kinase 1

UPR:

Unfolded protein response

XBP1:

x-box binding protein 1

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Acknowledgements:

Richard S. Blumberg receives support from NIH DK044319, DK051362, DK053056 and DK088199 and the Harvard Digestive Diseases Center DK034854.Michal F. Tomczak was supported by NIH T32DK007533 and currently receives support from Inflammatory Bowel Disease Working Group. Arthur Kaser receives support from the Austrian Science Fund and Ministry of Science P21530 and Y446, the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement no. 260961 and the National Institute for Health Research Cambridge Biomedical Research.

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  1. Div of Gastroenterology, Hepatology and Endoscopy, Dept of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis St, Thorn 1419, 02115, Boston, MA, USA

    Michal F. Tomczak & Richard S. Blumberg

  2. Div of Gastroenterology and Hepatology, Dept of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

    Arthur Kaser

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  1. Michal F. Tomczak
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  2. Arthur Kaser
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Correspondence to Richard S. Blumberg .

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  1. Dept Molec Cell Bio, K.U. Leuven, Harestraat/Gasthuisberg, B-3000 Leuven, 3000, Belgium

    Patrizia Agostinis

  2. School of Natural Science, Department of Biochemistry, NUI Galway, University Road, Galway, Ireland

    Samali Afshin

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Tomczak, M., Kaser, A., Blumberg, R. (2012). ER Stress in Intestinal Inflammatory Disease. In: Agostinis, P., Afshin, S. (eds) Endoplasmic Reticulum Stress in Health and Disease. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4351-9_12

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