The Role of Cytokines in the Fibrotic Responses in Crohn’s Disease

Curciarello, Renata; Docena, Guillermo Horacio; MacDonald, Thomas T.

doi:10.3389/fmed.2017.00126

Cited by 38 publications

(28 citation statements)

References 105 publications

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“…A randomized clinical trial showed no effects of anti-TNFα treatment on deep endometriosis-associated pain 18 . Various anti-TNFα agents have been used in clinical practice for the management of inflammatory bowel disease (IBD) for the last 20 years 46,47 . However, therapeutic strategies to block TNFα to prevent fibrostenosis in Crohn's disease have only been successful in animal models 48 .…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent pro- or anti-fibrotic responses of endometriotic stromal cells to interleukin-1β and tumor necrosis factor α

Matsuzaki

Pouly

Canis

2020

Sci Rep

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Endometriosis are characterized by dense fibrous tissue. Numerous studies have investigated roles of inflammation on the pathophysiology of endometriosis. However, the interplay of inflammation and fibrosis remains to be clarified. Here we show that low levels of interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNFα) promoted a fibrotic phenotype, whereas high levels of IL-1β and tnfα inactivated the fibrotic phenotype of endometriotic stromal cells (Ectopic-ES). IL-1β 10 pg/mL and TNFα 100 and 1,000 pg/mL had minimal effects, whereas the highest dose of IL-1β (100 pg/mL) significantly decreased collagen gel contraction in Ectopic-ES. Furthermore, in Ectopic-ES, low levels of IL-1β (1 pg/mL) and/or tnfα 10 pg/mL significantly increased Col I mRNA expression, whereas higher doses of IL-1β (10 and/ or 100 pg/mL) and/or TNFα (100 and/or 1,000 pg/mL) significantly decreased Col I and/or αSMA mRNA expression and the percentage of cells with Col I + and/or αSMA + stress fibers. In contrast, in either menstrual endometrial stromal cells of patients with endometriosis or those of healthy women, varying doses of IL-1β and/or TNFα had no significant effects on either Col I or αSMA mRNA/protein expression. The present findings bring into question whether we should still continue to attempt anti-inflammatory treatment strategies for endometriosis. Endometriosis, particularly deep infiltrating endometriosis and ovarian endometriosis, is histologically characterized by the presence of dense fibrous tissue 1-3. Previous studies including those from our group demonstrated that knowledge of the cellular and molecular mechanisms of fibrosis is indispensable for the development of strategies to prevent and treat this condition 4-12. Acute inflammatory reactions play an important part in triggering fibrosis in many different organ systems 13. Low-grade but persistent inflammation is also thought to contribute to the progression of fibrosis 13. In many fibrotic disorders, a persistent inflammatory trigger is crucial to the activation of the wound-healing process that leads to fibrosis 13. Endometriosis has been considered to be an immune-mediated chronic inflammatory disorder 14,15. Numerous studies have investigated the role of immune-mediated chronic inflammation on the pathophysiology of endometriosis 14,15 and attempted to evaluate various anti-inflammatory drugs, including tumor necrosis factor-alpha TNFα inhibitors 16-18 and cyclooxygenase-2 (Cox-2) inhibitors 19-21 , in endometriosis. However, the interplay between inflammation and fibrosis at the cellular and molecular levels in endometriosis pathophysiology remains to be clarified. Studies have suggested that repeated tissue injury and repair caused by recurrent menstrual bleeding induce inflammation, resulting in fibrosis in endometriosis 8,9. However, endometrial repair is normally scarless 22. It is not clear why repeated tissue injury and repair caused by recurrent menstrual bleeding do not induce fibrosis in the endometrium, whereas they do in endometriosis. Acco...

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Section: Discussionmentioning

confidence: 99%

Dose-dependent pro- or anti-fibrotic responses of endometriotic stromal cells to interleukin-1β and tumor necrosis factor α

Matsuzaki

Pouly

Canis

2020

Sci Rep

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“…There is evidence that the character of the inflammatory response changes over the course of IBD. Type 1 and type 17 immune responses are known to be involved in the induction of CD colitis 47 , 48 , while type 2 cytokines have been associated with tissue remodeling and more chronic fibrotic pathology 30 , 31 . Kugathasan et al found that a strong type 1 immune profile exhibited by the gut mucosa of CD patients experiencing their first symptoms shifts to a more type 2 polarized milieu in patients with long-standing disease 49 .…”

Section: Discussionmentioning

confidence: 99%

“…Although IL-13 has been reported to be an inflammatory stimulus in UC 26 , 27 , recent clinical studies found that anti-IL-13 therapy was not effective for UC patients 28 , 29 . While IL-13 is not known to be an initial driver of CD, it has been implicated in tissue remodeling and fibrosis in CD 30 , 31 . IL-13 and other type 2 cytokines are upregulated in response to tissue injury and are important for dampening inflammation and promoting wound resolution and repair 23 , 32 – 34 , requirements for recovery from both UC and CD.…”

Section: Introductionmentioning

confidence: 99%

Anti-IL-13Rα2 therapy promotes recovery in a murine model of inflammatory bowel disease

et al. 2019

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There continues to be a major need for more effective inflammatory bowel disease (IBD) therapies. IL-13Rα2 is a decoy receptor that binds the cytokine IL-13 with high affinity and diminishes its STAT6-mediated effector functions. Previously, we found that IL-13Rα2 was necessary for IBD in mice deficient in the anti-inflammatory cytokine IL-10. Here, we tested for the first time a therapeutic antibody specifically targeting IL-13Rα2. We also used the antibody and Il13ra2 −/− mice to dissect the role of IL-13Rα2 in IBD pathogenesis and recovery. Il13ra2 −/− mice were modestly protected from induction of dextran sodium sulfate (DSS)-induced colitis. Following a 7-day recovery period, Il13ra2 −/− mice or wild-type mice administered the IL-13Rα2-neutralizing antibody had significantly improved colon health compared to control mice. Neutralizing IL-13Rα2 to increase IL-13 bioavailability promoted resolution of IBD even if neutralization occurred only during recovery. To link our observations in mice to a large human cohort, we conducted a phenome-wide association study of a more active variant of IL-13 (R130Q) that has reduced affinity for IL-13Rα2. Human subjects carrying R130Q reported a lower risk for Crohn's disease. Our findings endorse moving anti-IL-13Rα2 into preclinical drug development with the goal of accelerating recovery and maintaining remission in Crohn's disease patients.

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“…When comparing intestinal tissue samples from fibrotic CD with UC and uninvolved intestinal tissue, IL-13 transcripts were highest in fibrotic CD, but the difference was not statistically significant [199]. Whether IL-13 is involved in CD-related complications such as intestinal stricturing and fistulizing disease, requires further investigations [198,200].…”

Section: Does the Increased Il-13 Response Contribute To Disease Pathmentioning

confidence: 99%

Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD

Tindemans

Joosse

Samsom

2020

Cells

110

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Infiltration of the lamina propria by inflammatory CD4+ T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4+ T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4+ T-cell populations is crucial to prevent uncontrolled CD4+ T-cell responses and subsequent intestinal tissue damage. While at steady state, T-cells display mainly a regulatory phenotype, increased in Th1, Th2, Th9, Th17, and Th17.1 responses, and reduced Treg and Tr1 responses have all been suggested to play a role in IBD pathophysiology. However, it is highly unlikely that all these responses are altered in each individual patient. With the rapidly expanding plethora of therapeutic options to inhibit inflammatory T-cell responses and stimulate regulatory T-cell responses, a crucial need is emerging for a robust set of immunological assays to predict and monitor therapeutic success at an individual level. Consequently, it is crucial to differentiate dominant inflammatory and regulatory CD4+ T helper responses in patients and relate these to disease course and therapy response. In this review, we provide an overview of how intestinal CD4+ T-cell responses arise, discuss the main phenotypes of CD4+ T helper responses, and review how they are implicated in IBD.

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The Role of Cytokines in the Fibrotic Responses in Crohn’s Disease

Cited by 38 publications

References 105 publications

Dose-dependent pro- or anti-fibrotic responses of endometriotic stromal cells to interleukin-1β and tumor necrosis factor α

Dose-dependent pro- or anti-fibrotic responses of endometriotic stromal cells to interleukin-1β and tumor necrosis factor α

Anti-IL-13Rα2 therapy promotes recovery in a murine model of inflammatory bowel disease

Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD

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