Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Scharl, Michael; Vavricka, Stephan R.; Rogler, Gerhard

doi:10.2174/13894501113149990159

Cited by 20 publications

(15 citation statements)

References 178 publications

(156 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, anti-TNF antibodies are a widely used treatment in IBD therapy, whereas IL-6 could also be a potential target for future therapeutics. IL-6 antibodies are currently used in clinical studies [24]. Cell lysates were analysed by real-time PCR and the levels of IL-6, IL-8 and TNF mRNA were normalised to the housekeeping gene, β-actin.…”

Section: Resultsmentioning

confidence: 99%

A Cell Type-Specific Role of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Regulating ER Stress Signalling

Kasper

Spalinger²,

Raselli³

et al. 2015

Digestion

Self Cite

View full text Add to dashboard Cite

Background/Aims: Genetic polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) have been associated with inflammatory bowel disease (IBD). A recent study demonstrated that PTPN2 regulates ER stress signalling in pancreatic β-cells. Therefore, we investigated whether PTPN2 regulates ER stress pathways, apoptosis and cytokine secretion in human intestinal epithelial cells (IECs) and monocytes. Methods: THP-1 and HT-29 IECs were stimulated with 2 µg/ml tunicamycin (TNM) for the indicated periods of time. For knockdown experiments, cells were transfected using a mixture of three different PTPN2-specific siRNA oligonucleotides. Cell lysates were analysed by Western blot and real-time PCR. Cytokine secretion was studied by ELISA measurements of cell culture supernatant. Results: TNM treatment reduced PTPN2 protein levels in HT-29 IECs and THP-1 monocytes. Knockdown of PTPN2 in THP-1 monocytes led to an exaggerated induction of phospho-eIF2α, enhanced PARP cleavage, indicative of apoptosis, and attenuated IL-8 and TNF secretion upon TNM stimulation. In HT-29 cells PTPN2 deficiency caused reduced phosphorylation of eIF2α and PARP cleavage under ER stress conditions. Conclusions: Whereas the knockdown of PTPN2 made THP-1 cells more susceptible to ER stress, PTPN2 deficiency reduced ER stress responses in HT-29 IECs. This suggests that PTPN2 regulates adaptation to ER stress in a cell type-specific manner.

show abstract

Section: Resultsmentioning

confidence: 99%

A Cell Type-Specific Role of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Regulating ER Stress Signalling

Kasper

Spalinger²,

Raselli³

et al. 2015

Digestion

Self Cite

View full text Add to dashboard Cite

show abstract

“…In 2013, we had the pleasure to write a review on new anti-cytokines for IBD 'What is in the pipeline?' [63] . Unfortunately, 2/3 of the anticytokines strategies that were in the pipeline at that time have failed and are no longer followed.…”

Section: The Promise Of Precision Medicinementioning

confidence: 99%

Anti-Cytokine Strategies beyond Anti-Tumour Necrosis Factor-α Therapy: Pathophysiology and Clinical Implications

Rogler

Biedermann

Scharl

2017

Dig Dis

Self Cite

View full text Add to dashboard Cite

Cytokines are small proteins produced by a broad range of cells important in cell signaling. They include interleukins, but also chemokines, interferons, and tumor necrosis factors (TNF). They play an important role for communication between cells of the innate and adaptive immune system. The cytokine network is complex and, therefore, therapeutic interventions are difficult. The first anti-cytokine strategy successfully introduced into IBD therapy was the neutralization of TNF by antibodies. Beyond targeting this cytokine anti-IL-23 strategies were demonstrated to be of therapeutic benefit in IBD. Anti-IL-6 strategies seem to have clinical potential but also cause some risk for the patient due to the lack of CRP increase upon severe inflammation. JAK inhibitors target the intracellular signaling of several cytokine receptors and represent a promising class of broader and somewhat unspecific anti-cytokine strategies. Many other anti-cytokine approaches have failed due to the redundant nature of the cytokine network. Whether further anti-cytokines strategies have potential for IBD treatment may be evaluated in future studies.

show abstract

“…Recent reviews suggest that many attempts to treat IBD have been unsuccessful [1,2]. This may be due to the fact that most recent attempts were based on the immune suppressive paradigm which actually treats the resulting inflammation but not the underlying causes which might be more an immunodeficiency or due to a leaky barrier and a disturbed interaction between host and the microbiome.…”

Section: Introductionmentioning

confidence: 99%

Trichuris suis Ova, Lecithin and Other Fancy Molecules

Schölmerich

2014

Dig Dis

View full text Add to dashboard Cite

During the last 20 years, treatment paradigms as well as drugs used for IBD have changed significantly. However, there are still many unmet needs and a significant number of patients needing better therapy. It is obvious from this situation that many attempts have been made to implement new drugs and treatment algorithms including biologicals, new formulations of old drugs and ‘fancy molecules or approaches'. For about 10 years, the application of Trichuris suis ova has been promoted and used in quite a number of patients. Two early studies suggested positive effects in ulcerative colitis as well as in Crohn's disease. These studies were based on experimental data in animal models as well as in vitro experiments. However, two large randomized controlled trials were not able to provide significant clinical effects in active Crohn's disease as compared to placebo, although a biological reaction (eosinophilia) was found. Another approach is the use of locally released phosphatidylcholine in ulcerative colitis. This approach is based on decreased phosphatidylcholine concentrations in the colonic mucus in patients, and showed positive effects in a number of monocentric trials in steroid-refractory and chronic active ulcerative colitis. A dose-finding study gave a positive signal in the highest-dose group and this approach is being tested further in controlled trials. Many other ‘fancy molecules' including cannabis, vitamin D, thalidomide, hyaluronic acid, lidocaine, clonidine, chondroitin sulfate, naltrexone and melatonin have been tested in patients with claims of success. For most of those, however, controlled data in appropriate studies are lacking. Many more substances have been used in animal models and are probably applied in individual patients. Results of preliminary studies on some of the molecules mentioned are presented.

show abstract

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Cited by 20 publications

References 178 publications

A Cell Type-Specific Role of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Regulating ER Stress Signalling

A Cell Type-Specific Role of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Regulating ER Stress Signalling

Anti-Cytokine Strategies beyond Anti-Tumour Necrosis Factor-α Therapy: Pathophysiology and Clinical Implications

Trichuris suis Ova, Lecithin and Other Fancy Molecules

Contact Info

Product

Resources

About