Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice

Bertolotti, Anne; Wang, Xiao Zhong; Novoa, Isabel; Jungreis, Rivka; Schlessinger, Karni; Cho, Judy H.; West, A. Brian; Ron, David

doi:10.1172/jci11476

Cited by 374 publications

(370 citation statements)

References 60 publications

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“…Consistent with this possibility, the UPR has been implicated in another animal model of colitis, induced by dextran sodium sulfate (38). Moreover, transfection of HLA-B27 has been shown to render human cell lines more susceptible to intracellular replication of bacteria such as Salmonella (39).…”

Section: Discussionmentioning

confidence: 80%

Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

Tran¹,

Dorris²,

Satumtira³

et al. 2006

Arthritis & Rheumatism

158

150

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Objective. Ankylosing spondylitis and related spondylarthritides are associated with HLA-B27, and also with intestinal inflammation, by unknown mechanisms. The folded HLA-B27 molecule is a trimer of heavy chain, ␤ 2 -microglobulin (␤ 2 m), and short peptide. However, B27 heavy chain has an unusual propensity to misfold and trigger the unfolded protein response (UPR). This study was initiated to test the hypothesis that B27 misfolding plays a role in the pathogenesis of spondylarthritis.Methods. Rats with high transgene copy numbers of HLA-B27 heavy chain together with human ␤ 2 m (Hu␤ 2 m) spontaneously develop colitis, peripheral arthritis, and occasional spondylitis, and those with lower transgene copy numbers remain healthy. We crossed disease-prone and healthy HLA-B27/Hu␤ 2 mtransgenic rat lines with a healthy line, 283-2, carrying only the Hu␤ 2 m transgene. HLA-B27 assembly was assessed by pulse-chase analysis of B27 molecules, and UPR triggering was assessed by measuring BiP/Grp78 messenger RNA (mRNA) in splenic concanavalin A blasts. Surface expression of B27 and Hu␤ 2 m was determined by flow cytometry. Disease manifestations were identified by clinical observation, histology, and measurement of cytokine mRNA.Results. The extra Hu␤ 2 m from the 283-2 line significantly reduced B27 misfolding and UPR triggering. Unexpectedly, however, F 1 male offspring of the healthy 21-3 line crossed with the 283-2 line showed a high prevalence, severity, and duration of arthritis and spondylitis, in the absence of colitis. The arthropathy showed many features characteristic of human spondylarthritis.Conclusion. These results suggest that B27 misfolding is associated with intestinal inflammation, but that neither B27 misfolding nor intestinal inflammation is critical to the development of B27-associated arthropathy.The spondylarthritides are a group of inflammatory rheumatic diseases characterized by axial and peripheral arthropathy and a variety of extraarticular lesions (1). In the prototype of these disorders, ankylosing spondylitis (AS), there is inflammation in the spinal and sacroiliac joints and in ligamentous attachments that, in severe cases, leads to bony fusion. The pathogenesis of spondylarthritis is poorly understood. Two factors strongly associated with these conditions are intestinal inflammation and the major histocompatibility complex (MHC) class I gene HLA-B27.With regard to the association with intestinal inflammation, the prevalence of inflammatory bowel disease (IBD) (both Crohn's disease and ulcerative colitis) is increased in individuals with AS. An even higher prevalence of IBD is found in individuals with other forms of spondylarthritis (2), and endoscopic studies with biopsy have shown a prevalence of microscopic inflammatory bowel lesions in 60-70% of patients

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Section: Discussionmentioning

confidence: 80%

Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

Tran¹,

Dorris²,

Satumtira³

et al. 2006

Arthritis & Rheumatism

158

150

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“…2 A). In addition to ubiquitously expressed Ire1, IECs express another isoform (Ire1) with the capacity to splice Xbp1 mRNA (Bertolotti et al, 2001). It is therefore remarkable that genetic co-deletion of Ire1 (Xbp1 /(IEC) ;Ern1 /(IEC) ) alone was sufficient to completely revert the massive splicing of Xbp1 mRNA to the baseline levels observed in Xbp1-sufficient IECs (Fig.…”

Section: Isc Expansion Is Dependent On Overactivation Of Ire1mentioning

confidence: 94%

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

Niederreiter¹,

Fritz²,

Adolph³

et al. 2013

J Cell Biol

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“…Within intestine, IRE1␤ protein is detectable in the stomach, small intestine, and colon. Furthermore, it is expressed mainly in the intestinal epithelial cells (15). By modulating MTP mRNA levels and, consequently, the extent of apoB lipidation, IRE1␤ may 1) protect the ER from the consequences of rapid fluctuations in membrane PL, neutral lipids, or vitamin E levels or 2) mediate downregulation of chylomicron secretion in response to satiety signals or respond to endocrine factors released by the liver and adipose tissue in the presence of excess accumulation of lipid throughout the body.…”

Section: Assembly Secretion and Regulation Of Intestinal Lipoproteinsmentioning

confidence: 99%

Intestinal lipid absorption

Iqbal¹,

Hussain²

2009

American Journal of Physiology-Endocrinology and Metabolism

648

484

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Our knowledge of the uptake and transport of dietary fat and fat-soluble vitamins has advanced considerably. Researchers have identified several new mechanisms by which lipids are taken up by enterocytes and packaged as chylomicrons for export into the lymphatic system or clarified the actions of mechanisms previously known to participate in these processes. Fatty acids are taken up by enterocytes involving protein-mediated as well as proteinindependent processes. Net cholesterol uptake depends on the competing activities of NPC1L1, ABCG5, and ABCG8 present in the apical membrane. We have considerably more detailed information about the uptake of products of lipid hydrolysis, the active transport systems by which they reach the endoplasmic reticulum, the mechanisms by which they are resynthesized into neutral lipids and utilized within the endoplasmic reticulum to form lipoproteins, and the mechanisms by which lipoproteins are secreted from the basolateral side of the enterocyte. apoB and MTP are known to be central to the efficient assembly and secretion of lipoproteins. In recent studies, investigators found that cholesterol, phospholipids, and vitamin E can also be secreted from enterocytes as components of high-density apoB-free/apoAI-containing lipoproteins. Several of these advances will probably be investigated further for their potential as targets for the development of drugs that can suppress cholesterol absorption, thereby reducing the risk of hypercholesterolemia and cardiovascular disease.intestine; dietary fat; triacylglycerol; cholesterol; phospholipids; fat-soluble vitamins; microsomal triglyceride transfer protein DIETARY FATS CONSIST OF A WIDE ARRAY of polar and nonpolar lipids (32, 33). Triacylglycerol (TAG) is the dominant fat in the diet, contributing 90 -95% of the total energy derived from dietary fat. Dietary fats also include phospholipids (PLs), sterols (e.g., cholesterol), and many other lipids (e.g., fatsoluble vitamins). The predominant PL in the intestinal lumen is phosphatidylcholine (PC), which is derived mostly from bile (10 -20 g/day in humans) but also from the diet (ϳ1-2 g/day). The predominant dietary sterols are cholesterol (mostly of animal origin) and ␤-sitosterol (the major plant sterol). Although ␤-sitosterol accounts for 25% of dietary sterols, it is not absorbed by humans under physiological conditions.Researchers have been investigating the various steps involved in lipid digestion, absorption, and metabolism to identify factors that could serve as targets for the development of drugs capable of reducing the risk of lipid-associated disorders, including dyslipidemias and cardiovascular disease. In so doing, they have explored key aspects of lipid digestion hydrolysis, emulsification, and micelle formation. They have also explored key issues of absorption, e.g., the uptake of the products of lipid hydrolysis by enterocytes (the epithelial cells lining the walls of the intestinal lumen) and their transport to intracellular compartments, where fatty acids and sterols are...

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Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice

Cited by 374 publications

References 60 publications

Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

Intestinal lipid absorption

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Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice

Cited by 374 publications

References 60 publications

Additional human β2‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

Additional human β2‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

Intestinal lipid absorption

Contact Info

Product

Resources

About

Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

Additional human β₂‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats