Archive for the ‘Crohn’s disease’ Category

Al is on the way to lead critical ED decisions on CT

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc

Artificial intelligence (AI) has infiltrated many organizational processes, raising concerns that robotic systems will eventually replace many humans in decision-making. The advent of AI as a tool for improving health care provides new prospects to improve patient and clinical team’s performance, reduce costs, and impact public health. Examples include, but are not limited to, automation; information synthesis for patients, “fRamily” (friends and family unpaid caregivers), and health care professionals; and suggestions and visualization of information for collaborative decision making.

In the emergency department (ED), patients with Crohn’s disease (CD) are routinely subjected to Abdomino-Pelvic Computed Tomography (APCT). It is necessary to diagnose clinically actionable findings (CAF) since they may require immediate intervention, which is typically surgical. Repeated APCTs, on the other hand, results in higher ionizing radiation exposure. The majority of APCT performance guidance is clinical and empiric. Emergency surgeons struggle to identify Crohn’s disease patients who actually require a CT scan to determine the source of acute abdominal distress.

Image Courtesy: Jim Coote via Pixabay https://www.aiin.healthcare/media/49446

Aid seems to be on the way. Researchers employed machine learning to accurately distinguish these sufferers from Crohn’s patients who appear with the same complaint but may safely avoid the recurrent exposure to contrast materials and ionizing radiation that CT would otherwise wreak on them.

The study entitled “Machine learning for selecting patients with Crohn’s disease for abdominopelvic computed tomography in the emergency department” was published on July 9 in Digestive and Liver Disease by gastroenterologists and radiologists at Tel Aviv University in Israel.

Retrospectively, Jacob Ollech and his fellow researcher have analyzed 101 emergency treatments of patients with Crohn’s who underwent abdominopelvic CT.

They were looking for examples where a scan revealed clinically actionable results. These were classified as intestinal blockage, perforation, intra-abdominal abscess, or complex fistula by the researchers.

On CT, 44 (43.5 %) of the 101 cases reviewed had such findings.

Ollech and colleagues utilized a machine-learning technique to design a decision-support tool that required only four basic clinical factors to test an AI approach for making the call.

The approach was successful in categorizing patients into low- and high-risk groupings. The researchers were able to risk-stratify patients based on the likelihood of clinically actionable findings on abdominopelvic CT as a result of their success.

Ollech and co-authors admit that their limited sample size, retrospective strategy, and lack of external validation are shortcomings.

Moreover, several patients fell into an intermediate risk category, implying that a standard workup would have been required to guide CT decision-making in a real-world situation anyhow.

Consequently, they generate the following conclusion:

We believe this study shows that a machine learning-based tool is a sound approach for better-selecting patients with Crohn’s disease admitted to the ED with acute gastrointestinal complaints about abdominopelvic CT: reducing the number of CTs performed while ensuring that patients with high risk for clinically actionable findings undergo abdominopelvic CT appropriately.

Main Source:

Konikoff, Tom, Idan Goren, Marianna Yalon, Shlomit Tamir, Irit Avni-Biron, Henit Yanai, Iris Dotan, and Jacob E. Ollech. “Machine learning for selecting patients with Crohn’s disease for abdominopelvic computed tomography in the emergency department.” Digestive and Liver Disease (2021). https://www.sciencedirect.com/science/article/abs/pii/S1590865821003340

Other Related Articles published in this Open Access Online Scientific Journal include the following:

Al App for People with Digestive Disorders

Reporter: Irina Robu, Ph.D.


Machine Learning (ML) in cancer prognosis prediction helps the researcher to identify multiple known as well as candidate cancer diver genes

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc


Al System Used to Detect Lung Cancer

Reporter: Irina Robu, Ph.D.


Artificial Intelligence: Genomics & Cancer


Yet another Success Story: Machine Learning to predict immunotherapy response

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc


Systemic Inflammatory Diseases as Crohn’s disease, Rheumatoid Arthritis and Longer Psoriasis Duration May Mean Higher CVD Risk

Reporter: Aviva Lev-Ari, PhD, RN


Autoimmune Inflammatory Bowel Diseases: Crohn’s Disease & Ulcerative Colitis: Potential Roles for Modulation of Interleukins 17 and 23 Signaling for Therapeutics

Curators: Larry H Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN https://pharmaceuticalintelligence.com/2016/01/23/autoimmune-inflammtory-bowl-diseases-crohns-disease-ulcerative-colitis-potential-roles-for-modulation-of-interleukins-17-and-23-signaling-for-therapeutics/

Inflammatory Disorders: Inflammatory Bowel Diseases (IBD) – Crohn’s and Ulcerative Colitis (UC) and Others

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


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Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

Curator: Stephen J. Williams, PhD 

Below is a series of posts and articles related to the role of G protein coupled receptors (GPCR) in various chronic diseases.  This is only a cursory collection and by no means represents the complete extensive literature on pathogenesis related to G protein function or alteration thereof.  However it is important to note that, although we think of G protein signaling as rather short lived, quick, their chronic activation may lead to progression of various disease. As to whether disease onset, via GPCR, is a result of sustained signal, loss of desensitization mechanisms, or alterations of transduction systems is an area to be investigated.


Molecular Pathogenesis of Progressive Lung Diseases

Author: Larry H. Bernstein, MD, FCAP


Chronic Obstructive Lung Disease (COPD)

Inflammatory and infectious factors are present in diseased airways that interact with G-protein coupled receptors (GPCRs), such as purinergic receptors and bradykinin (BK) receptors, to stimulate phospholipase C [PLC]. This is followed by the activation of inositol 1,4,5-trisphosphate (IP3)-dependent activation of IP3 channel receptors in the ER, which results in channel opening and release of stored Ca2+ into the cytoplasm. When ER Ca2+ stores are depleted a pathway for Ca2+ influx across the plasma membrane is activated. This has been referred to as “capacitative Ca2+ entry”, and “store-operated calcium entry” (3). In the next step PLC mediated Ca2+ i is mobilized as a result of GPCR activation by inflammatory mediators, which triggers cytokine production by Ca2+ i-dependent activation of the transcription factor nuclear factor kB (NF-kB) in airway epithelia.




In Alzheimer’s Disease

Important Lead in Alzheimer’s Disease Model

Larry H. Bernstein, MD, FCAP, Curator discusses findings from a research team at University of California at San Diego (UCSD) which the neuropeptide hormone corticotropin-releasing factor (CRF) as having an important role in the etiology of Alzheimer’s Disease (AD). CRF activates the CRF receptor (a G stimulatory receptor).  It was found inhibition of the CRF receptor prevented cognitive impairment in a mouse model of AD.  Furthermore researchers at the Flanders Interuniversity Institute for Biotechnology found the loss of a protein called G protein-coupled receptor 3 (GPR3) may lower the amyloid plaque aggregation, resulting in improved cognitive function.  Additionally inhibition of several G-protein coupled receptors alter amyloid precursor processing, providing a further mechanism of the role of GPCR in AD (see references in The role of G protein-coupled receptors in the pathology of Alzheimer’s disease by Amantha Thathiah and Bart De Strooper Nature Reviews Feb 2011; 12: 73-87 and read post).


In Cardiovascular and Thrombotic Disease


Adenosine Receptor Agonist Increases Plasma Homocysteine


and read related articles in curation on effects of hormones on the cardiovascular system at

Action of Hormones on the Circulation


In Cancer

A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial


Further curations and references of G proteins and chronic disease can be found at the Open Access journal https://pharmaceuticalintelligence.com using the search terms “GCPR” and “disease” in the Search box in the upper right of the home page.







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Inflammatory Disorders: Articles published @ pharmaceuticalintelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

This is a compilation of articles on Inflammatory Disorders that were published 

@ pharmaceuticalintelligence.com, since 4/2012 to date

There are published works that have not been included.  However, there is a substantial amount of material in the following categories:

  1. The systemic inflammatory response
  2. sepsis
  3. vasculitis
  4. neurodegenerative disease
  5. cancer immunology
  6. autoimmune diseases: rheumatoid arthritis, colitis, ileitis, …
  7. T cells in immunity

Proteomics, metabolomics and diabetes

























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Intestinal inflammatory pharmaceutics

Curator: Larry H. Bernstein, MD, FCAP

AbbVie Invests in Synthetic Microbes for Treatment of Intestinal Disorders

Aaron Krol    http://www.bio-itworld.com/2016/2/10/abbvie-invests-synthetic-microbes-treatment-intestinal-disorders.html

Intestinal Inflammatory Pharmaceutics, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair

February 10, 2016 | This morning, AbbVie announced a partnership with Synlogic of Cambridge, Mass., to create microbiome-based therapies for the treatment of inflammatory bowel disease (IBD). The two companies have sketched out a suggested three-year timeline for preclinical research and development, after which AbbVie will take over advancing any drug candidates into clinical trials.

Drugs inspired by the microbes that live in the human gut are a hot topic in biotech. Companies like Seres Health and Vedanta Biosciences are pursuing the idea from a variety of angles, from making traditional small molecule drugs that interact with the microbiome, to creating probiotics or microbial cocktails that restore a healthy balance to the gut ecosystem. IBD, including Crohn’s disease and ulcerative colitis, is an especially popular target for these companies, thanks to strong suggestions that bacterial populations can affect the course of the disease. Already, Second Genome and Coronado Biosciences have taken prospective treatments into the clinic (though the latter has been dealt serious setbacks in Phase II trials).

But even among this peculiar batch of startups, Synlogic’s approach to drug design is exquisitely odd. The company calls its products “synthetic biotics”―in fact, they’re genetically engineered bacteria whose DNA contains intricately designed “gene circuits,” built to start producing therapeutic molecules when and only when the patient needs them.

“We are not looking at correcting the dysregulation of microbes in the gut, like other microbiome companies,” CEO José-Carlos Gutiérrez-Ramos tells Bio-IT World. “We have one bacterium, and it’s engineered to do different functions.”

Synlogic was founded in 2013 by two synthetic biologists at MIT, Timothy Lu and Jim Collins. (Bio-IT World has previously spoken with Lu about his academic work on bacterial gene circuits.) Gutiérrez-Ramos joined almost two years later, leaving a position as the head of Pfizer’s BioTherapeutics R&D group, where he had plenty of opportunity to turn emerging biotechnology ideas into drug candidates ready for submission to the FDA.

Still, synthetic biotics are a good deal more unusual than the biologic drugs he worked on at Pfizer.

His new company doesn’t quite spin functions for its microbes out of whole cloth. All the genes the company uses are copied either from the human genome, or from the bacteria living inside us. But by recombining those genes into circuits, Gutiérrez-Ramos believes Synlogic can finely control whether and when genes are expressed, giving its synthetic biotics the same dosage control as a traditional drug. Meanwhile, choosing the right bacterium to engineer―the current favorite is a strain called E. coli Nissle―ensures the biotics do not form stable colonies in the gut, but can be cleared out as soon as a patient stops treatment.

“We’re pharma guys,” he says. “What we want is to have pharmacologically well-defined products.”

The Molecular Circuit Board

Even before the partnership with AbbVie, Synlogic had a pipeline of drug candidates in development, all meant to treat rare genetic disorders caused by single mutations that shut down the activity of a crucial gene. In principle, there seems to be no reason that bacteria carrying the right genes couldn’t pick up the slack. “We know the patient is missing a function that is typically performed by the liver, or the kidney, or the pancreas,” says Gutiérrez-Ramos. “What we do is shift that function from an organ to a stable fraction of the microbiome.”

The approach is in some ways analogous to gene therapy, where a corrected version of a broken gene is inserted into a patient’s own DNA. “We don’t use that word, but the fact is it’s a non-somatic gene therapy,” Gutiérrez-Ramos says. “And if something goes wrong, you can control it just by stopping treatment.” The most advanced synthetic biotic in Synlogic’s pipeline targets urea cycle disorder, exactly the sort of disease that might otherwise be addressed by gene therapy: patients are missing a single enzyme that helps remove nitrogen from the body and prevent it from forming ammonia in the bloodstream. Synlogic will meet with the FDA this March to discuss whether and how this first product can be tested in humans.

Gutierrez Ramos

The new IBD program with AbbVie, however, adds a whole new level of complexity. Executives from the two companies have been in discussions for around six months, and both agree that no single mechanism will be enough to provide significant relief for patients. Crohn’s and ulcerative colitis are painful autoimmune diseases that involve both a weakening of the epithelial lining in the stomach, and a buildup of inflammatory molecules. The development plan that AbbVie and Synlogic have agreed on includes three separate methods of attack to relieve these symptoms.

“One approach AbbVie is very interested in is for our synthetic biotics to produce substances that could tighten the epithelial barrier,” says Gutiérrez-Ramos. “Another approach is to degrade pro-inflammatory molecules”―the same tack taken by AbbVie’s current leading IBD drug, Humira, which targets the inflammatory protein TNFα. “Finally, we can produce anti-inflammatory molecules.”

Uniquely, synthetic biotics can perform all three functions at once; it’s just a matter of inserting the right genes. But that alone might not be a decisive advantage over some sort of combination therapy. The biggest selling point of Synlogic’s microbes is not the genes they can be engineered to express―what you might call the “output” of their gene circuits―but the input, the DNA elements called “inducible promoters” that decide when those genes should be activated.

The core idea is that patients will have a constant population of synthetic biotics in their bodies, taken daily―but those microbes will only generate their therapeutic payloads when needed. In IBD, Gutiérrez-Ramos explains, “it’s not that the patient is always inflamed, but they have flares. Our vision, and AbbVie’s vision, is that the bacteria that you take every day sense when the flare is coming, and then trigger the genetic output.”

This would be a major improvement over a drug like Humira, which after all is constantly inhibiting a part of the immune system. Patients taking Humira, or one of the many other immunosuppressant drugs for IBD, are at a constantly heightened risk of infection; tuberculosis is a particular specter for these patients. If Synlogic can find a genetic “on-switch” that responds to a reliable indicator of IBD flares, it could potentially create a much more precisely administered treatment, while still giving patients the simple dosing schedule of one pill every day.

The company has leads on two inducible promoters that might do the trick: one that reacts to nitric oxide, and another tied to reactive oxygen species. Of course, there’s no guarantee that either will respond sensitively to IBD flares in a real clinical setting. “This is an early time for the technology,” says Gutiérrez-Ramos. “We have demonstrated this in animals, but we have to demonstrate it in humans.”

Although it’s far too early to say if synthetic biotics will become an ordinary part of the pharma toolkit, AbbVie’s decision to invest in the technology offers the means to test this approach on a large scale. Synlogic expects to raise its own funding for trials of its rare disease products, which the FDA does not expect to enroll huge numbers of patients, but IBD is a problem of a very different order.

“We are very honored to work with truly the leader in treatment of inflammatory bowel disease,” says Gutiérrez-Ramos. With the backing of big pharma, it will be possible to trial microbiome-based therapies for the kinds of common, chronic diseases that are the biggest drain on our healthcare system. What’s more, the AbbVie partnership is an important signal of the industry’s faith in synthetic biology as an approach to treating disease.

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Autoimmune Inflammtory Bowel Diseases: Crohn’s Disease & Ulcerative Colitis – Potential Roles for Modulation of Interleukins 17 and 23 Signaling for Therapeutics


Curators: Larry H Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN


Edited: 1/25/2016


Sarepta Therapeutics, Corvallis, Oregon, has been assigned a patent (9,238,042) – “antisense modulation of interleukins 17 and 23 signaling.”

01/21/2016 | 07:08am US/Eastern
By Targeted News Service

ALEXANDRIA, Va., Jan. 21 — Sarepta Therapeutics, Corvallis, Oregon, has been assigned a patent (9,238,042) developed by four co-inventors for “antisense modulation of interleukins 17 and 23 signaling.” The co-inventors are Frederick J. Schnell, Corvallis, Oregon, Patrick L. Iversen, Corvallis, Oregon, Dan V. Mourich, Albany, Oregon, and Gunnar J. Hanson, Bothell, Washington.

The patent application was filed on May 13, 2011 (13/107,528). The full-text of the patent can be found at


Written by Deviprasad Jena; edited by Jaya Anand.


Sarepta Therapeutics Corvallis

United States Patent 9,238,042
Schnell ,   et al. January 19, 2016

Antisense modulation of interleukins 17 and 23 signaling

Abstract  Provided are antisense oligonucleotides and other agents that target and modulate IL-17 and/or IL-23 signaling activity in a cell, compositions that comprise the same, and methods of use thereof. Also provided are animal models for identifying agents that modulate 17 and/or IL-23 signaling activity.



On PubMed

Immunity. 2015 Oct 20;43(4):739-50. doi: 10.1016/j.immuni.2015.08.019. Epub 2015 Sep 29.

Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation.


Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of both of these cytokines is effective for treating psoriasis, IL-12 and IL-23 p40 inhibition attenuates Crohn’s disease, whereas IL-17A or IL-17 receptor A (IL-17RA) inhibition exacerbates Crohn’s disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the multidrug resistance-1a-ablated (Abcb1a(-/-)) mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing regulatory T (Treg) cell accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provide insight into mechanisms underlying exacerbation of Crohn’s disease when IL-17A or IL-17RA is inhibited.

Copyright © 2015 Elsevier Inc. All rights reserved.

[PubMed – in process]
Immunity. 2015 Oct 20;43(4):620-2. doi: 10.1016/j.immuni.2015.10.001.

Gut-Busters: IL-17 Ain’t Afraid of No IL-23.


Interleukin-23 (IL-23) is considered a critical regulator of IL-17 in lymphocytes. Whereas antibodies targeting IL-23 ameliorate colitis, IL-17 neutralization exacerbates disease. In this issue, Cua and colleagues and Maxwell and colleagues show that IL-17 maintains intestinal barrier integrity, helping explain this dichotomy (Lee et al., 2015; Maxwell et al., 2015).

Copyright © 2015 Elsevier Inc. All rights reserved.

[PubMed – in process]




Gut. 2014 Dec;63(12):1902-12. doi: 10.1136/gutjnl-2013-305632. Epub 2014 Feb 17.

Involvement of interleukin-17A-induced expression of heat shock protein 47 in intestinal fibrosis in Crohn’s disease.

Honzawa Y1Nakase H1Shiokawa M1Yoshino T1Imaeda H2Matsuura M1Kodama Y1Ikeuchi H3,Andoh A2Sakai Y4Nagata K5Chiba T1.

Author information



Intestinal fibrosis is a clinically important issue in Crohn’s disease (CD). Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone involved in fibrotic diseases. The molecular mechanisms of HSP47 induction in intestinal fibrosis related to CD, however, remain unclear. Here we investigated the role of interleukin (IL)-17A-induced HSP47 expression in intestinal fibrosis in CD.


Expressions of HSP47 and IL-17A in the intestinal tissues of patients with IBD were determined. HSP47 and collagen I expressions were assessed in intestinal subepithelial myofibroblasts (ISEMFs) isolated from patients with IBD and CCD-18Co cells treated with IL-17A. We examined the role of HSP47 in IL-17A-induced collagen I expression by administration of short hairpin RNA (shRNA) to HSP47 and investigated signalling pathways of IL-17A-induced HSP47 expression using specific inhibitors in CCD-18Co cells.


Gene expressions of HSP47 and IL-17A were significantly elevated in the intestinal tissues of patients with active CD. Immunohistochemistry revealed HSP47 was expressed in α-smooth muscle actin (α-SMA)-positive cells and the number of HSP47-positive cells was significantly increased in the intestinal tissues of patients with active CD. IL-17A enhanced HSP47 and collagen I expressions in ISEMFs and CCD-18Co cells. Knockdown of HSP47 in these cells resulted in the inhibition of IL-17A-induced collagen I expression, and analysis of IL-17A signalling pathways revealed the involvement of c-Jun N-terminal kinase in IL-17A-induced HSP47 expression.


IL-17A-induced HSP47 expression is involved in collagen I expression in ISEMFs, which might contribute to intestinal fibrosis in CD.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.


Crohn’s disease (CD); Fibrosis; Heat shock protein (HSP); Myofibroblasts



[PubMed – indexed for MEDLINE]



Dr. Larry H Bernstein voice on

Involvement of interleukin-17A-induced expression of heat shock protein 47

The tie is very interesting.  The IL17A association with fibrosis in Crohn’s may be unrelated to UC.  Ulcerative colitis only affects the superficial mucosa.  This is where the GI people have not been specific enough.  It is also the case that UC can extend to the ligament of Treitz, that separates small and large bowel.  I can’t grasp it all and have not had to think about this for perhaps a decade.  

The points of interest are:

1) the circulation of the small bowel, ascending and transverse colon are superior mesenteric artery. (I don’t recall if it is to midtransverse colon).

2) the circulation to the descending colon is the inferior mesenteric artery.

3) this might have some bearing on the issue of oxidative stress.  

The microbiome resides in the large intestine, which seems to work in concert with the microbiome with respect to E. coli and enterobacter.  In this case you only get superficial mucosal erosion, which is by no means not serious, but not associated with deep invasion of the muscularis.  

The deeply invasive Crohn’s regional enteritis may extend as far as the midtransverse colon, but not as a rule.  Isn’t it interesting that the more invasive disease is not at the “home” of the microbiome.  

There has been very interesting research reported in the Sunday NY Times about the “autopsy” and determining the time of death. There is a postmortem transition in the microbiome referred to as the “necrobiome”.   


Inflamm Bowel Dis. 2008 Sep;14(9):1197-204. doi: 10.1002/ibd.20482.

Transcriptomic analysis of intestinal fibrosis-associated gene expression in response to medical therapy in Crohn’s disease.

Burke JP1Ferrante MDejaegher KWatson RWDocherty NGDe Hertogh GVermeire SRutgeerts P,D’Hoore APenninckx FGeboes KVan Assche GO’Connell PR.

Author information



Glucocorticoids and monoclonal antibodies to tumor necrosis factor reduce inflammation in Crohn’s disease (CD). Rapid luminal healing, however, may promote intestinal stricture formation. The aim of this study was to examine fibrosis-associated gene expression in the intestine of patients with CD and correlate expression levels with prior medical therapies.


In all, 37 patients with stricturing CD and 18 non-CD controls underwent a transmural biopsy at the time of elective intestinal resection. Quantitative real-time polymerase chain reaction (PCR) was conducted to determine differential mRNA expression of TGF-beta(1), Smad-7, CTGF, collagen-1alpha, fibronectin, BMP-7, and MIF. Intestinal fibroblasts were treated in vitro with dexamethasone.


Relative to control, strictured CD intestinal tissue expressed increased TGF-beta(1), CTGF, collagen-1alpha, and BMP-7 (all P < 0.05). TGF-beta(1) gene expression positively correlated with the expression of its downstream targets (all P < 0.001). Preoperative infliximab exposure was not associated with increased expression in any of the target genes nor did the number of infliximab infusions correlate with gene expression. The number of cycles of corticosteroid treatment preoperatively was positively associated with CTGF (r = 0.486, P = 0.016) and MIF (r = 0.524, P = 0.009) expression. Intestinal fibroblasts treated in vitro with dexamethasone upregulated CTGF expression (P = 0.023).


Exposure to infliximab does not appear to induce a profibrotic transcriptional response in the CD intestine. Previous corticosteroid treatment is associated with increased expression of CTGF and MIF. Treating intestinal fibroblasts in vitro with steroids upregulates CTGF expression.

PMID: 18452219

[PubMed – indexed for MEDLINE]





J Interferon Cytokine Res. 2013 Jul;33(7):355-68. doi: 10.1089/jir.2012.0063. Epub 2013 Mar 8.

IL-23/IL-17A axis correlates with the nitric oxide pathway in inflammatory bowel disease: immunomodulatory effect of retinoic acid.

Rafa H1Saoula HBelkhelfa MMedjeber OSoufli IToumi Rde Launoit YMoralès ONakmouche M,Delhem NTouil-Boukoffa C.

Author information


Inflammatory bowel diseases (IBDs) are chronic inflammatory diseases of the gastrointestinal tract, which are clinically present as 1 of the 2 disorders, Crohn’s disease (CD) or ulcerative colitis (UC) (Rogler 2004). The immune dysregulation in the intestine plays a critical role in the pathogenesis of IBD, involving a wide range of molecules, including cytokines. The aim of this work was to study the involvement of T-helper 17 (Th17) subset in the bowel disease pathogenesis by the nitric oxide (NO) pathway in Algerian patients with IBD. We investigated the correlation between the proinflammatory cytokines [(interleukin (IL)-17, IL-23, and IL-6] and NO production in 2 groups of patients. We analyzed the expression of messenger RNAs (mRNAs) encoding Th17 cytokines, cytokine receptors, and NO synthase 2 (NOS2) in plasma of the patients. In the same way, the expression of p-signal transducer and activator of transcription 3 (STAT3) and NOS2 was measured by immunofluorescence and immunohistochemistry. We also studied NO modulation by proinflammatory cytokines (IL-17A, IL-6, tumor necrosis factor α, or IL-1β) in the presence or absence of all-trans retinoic acid (At RA) in peripheral blood mononuclear cells (PBMCs), monocytes, and in colonic mucosa cultures. Analysis of cytokines, cytokine receptors, and NOS2 transcripts revealed that the levels of mRNA transcripts of the indicated genes are elevated in all IBD groups. Our study shows a significant positive correlation between the NO and IL-17A, IL-23, and IL-6 levels in plasma of the patients with IBD. Interestingly, the correlation is significantly higher in patients with active CD. Our study shows that both p-STAT3 and inducible NOS expression was upregulated in PBMCs and colonic mucosa, especially in patients with active CD. At RA downregulates NO production in the presence of proinflammatory cytokines for the 2 groups of patients. Collectively, our study indicates that the IL-23/IL-17A axis plays a pivotal role in IBD pathogenesis through the NO pathway.

PMID: 23472658

[PubMed – indexed for MEDLINE]





Inflamm Bowel Dis. 2014 Jul;20(7):1250-8. doi: 10.1097/MIB.0000000000000043.

Mechanisms that mediate the development of fibrosis in patients with Crohn’s disease.


Crohn’s disease is complicated by the development of fibrosis and stricture in approximately 30% to 50% of patients over time. The pathogenesis of fibrostenotic disease is multifactorial involving the activation of mesenchymal cells by cytokines, growth factors, and other mediators released by immune cells, epithelial cells, and mesenchymal cells. Transforming growth factor β, a key activator of mesenchymal cells, is central to the process of fibrosis and regulates numerous genes involved in the disordered wound healing including collagens, and other extracellular matrix proteins, connective tissue growth factor, and insulin-like growth factors. The activated mesenchymal compartment is expanded by recruitment of new mesenchymal cells through epithelial to mesenchymal transition, endothelial to mesenchymal transition, and invasion of circulating fibrocytes. Cellular hyperplasia and increased extracellular matrix production, particularly collagens, from fibroblasts, myofibroblasts, and smooth muscle cells add to the disturbed architecture and scarring on the intestine. Extracellular matrix homeostasis is further disrupted by alterations in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinase in the gut. Among the 163 susceptibility genes identified that contribute to susceptibility in inflammatory bowel disease mutations in NOD2/CARD15, innate immune system components and autophagy jointly contribute to the activation of mesenchymal cells and pathogenesis of fibrosis in this polygenic disorder. Numerous growth factors cytokines and other mediators also contribute to development of fibrosis in the susceptible patient. This review focuses on the molecular mechanisms that regulate mesenchymal cell function, particularly smooth muscle cells, the largest compartment of mesenchyme in the intestine, that lead to fibrosis in Crohn’s disease.

[PubMed – indexed for MEDLINE]







On Crohn’s


  1. Cytokines in Crohn’s colitis.

Sher ME, D’Angelo AJ, Stein TA, Bailey B, Burns G, Wise L.

Am J Surg. 1995 Jan;169(1):133-6.

PMID: 7817982 [PubMed – indexed for MEDLINE]

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  1. Increased production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 by inflamed mucosa in inflammatory bowel disease.

Louis E, Ribbens C, Godon A, Franchimont D, De Groote D, Hardy N, Boniver J, Belaiche J, Malaise M.

Clin Exp Immunol. 2000 May;120(2):241-6.

PMID: 10792371 [PubMed – indexed for MEDLINE] Free PMC Article

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  1. In vitro effects of oxpentifylline on inflammatory cytokine release in patients with inflammatory bowel disease.

Reimund JM, Dumont S, Muller CD, Kenney JS, Kedinger M, Baumann R, Poindron P, Duclos B.

Gut. 1997 Apr;40(4):475-80.

PMID: 9176074 [PubMed – indexed for MEDLINE] Free PMC Article

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  1. Expression of interleukin-8 gene in inflammatory bowel disease is related to the histological grade of active inflammation.

Mazzucchelli L, Hauser C, Zgraggen K, Wagner H, Hess M, Laissue JA, Mueller C.

Am J Pathol. 1994 May;144(5):997-1007.

PMID: 8178948 [PubMed – indexed for MEDLINE] Free PMC Article

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On Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation

  1. Neutralizing IL-23 is superior to blocking IL-17 in suppressing intestinal inflammation in a spontaneous murine colitis model.

Wang R, Hasnain SZ, Tong H, Das I, Che-Hao Chen A, Oancea I, Proctor M, Florin TH, Eri RD, McGuckin MA.

Inflamm Bowel Dis. 2015 May;21(5):973-84. doi: 10.1097/MIB.0000000000000353.

PMID: 25803508 [PubMed – in process]

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  1. IL-17A signaling in colonic epithelial cells inhibits pro-inflammatory cytokine production by enhancing the activity of ERK and PI3K.

Guo X, Jiang X, Xiao Y, Zhou T, Guo Y, Wang R, Zhao Z, Xiao H, Hou C, Ma L, Lin Y, Lang X, Feng J, Chen G, Shen B, Han G, Li Y.

PLoS One. 2014 Feb 25;9(2):e89714. doi: 10.1371/journal.pone.0089714. eCollection 2014.

PMID: 24586980 [PubMed – indexed for MEDLINE] Free PMC Article

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