Regulation of eotaxin-3/CC chemokine ligand 26 expression by T helper type 2 cytokines in human colonic myofibroblasts

Takahashi, Kenichiro; Imaeda, Hirotsugu; Fujimoto, Takehide; Ban, Hiromitsu; Bamba, Shigeki; Tsujikawa, Tomoyuki; Sasaki, Makoto; Fujiyama, Yoshihide; Andoh, Akira

doi:10.1111/cei.12117

Cited by 25 publications

(22 citation statements)

References 35 publications

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“…(56) Another study of colonic myofibroblasts has shown that type-2 cytokines regulate the eosinophil-chemokine eotaxin-3 expression. (57) Here we provide evidence for the first time that eosinophils and in addition IL-33-stimulated eosinophils induce intestinal fibroblast production of proinflammatory cytokines TNF-α, IL-1β and IL-6 and eosinophilic-chemokines eotaxin-2 (CCL24) and eotaxin-3 (CCL26). Thus IL-33-eosinophil-fibroblast interactions may act to perpetuate intestinal inflammation and eosinophilia by both cytokine and chemokine production.…”

Section: Discussionmentioning

confidence: 71%

Eosinophils and IL-33 Perpetuate Chronic Inflammation and Fibrosis in a Pediatric Population with Stricturing Crohnʼs Ileitis

Masterson

Capocelli

Hosford

et al. 2015

Inflammatory Bowel Diseases

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Background Fibrostenosis and stricture are well-recognized endpoints in Crohn’s disease (CD). We hypothesized that stricturing-CD is characterized by eosinophilia and epithelial-IL-33. We proposed that eosinophil exposure to IL-33 would perpetuate inflammatory chronicity and subsequent fibrostenosis. Methods We performed a retrospective study of 74 children with inflammatory and stricturing ileal-CD comparing clinicopathological features to immunohistochemical measures of eosinophilia and IL-33. To scrutinize eosinophil patterns we developed a novel eosinophil-peroxidase (EPX)-score encompassing number, distribution and degranulation. Human eosinophils and intestinal fibroblasts were cultured with IL-33 and IL-13 and inflammatory and remodeling parameters were assessed. Anti-eosinophil therapy was also administered to the Crohn’s-like ileitis model (SAMP1/SkuSlc). Results Our novel EPX-score was more sensitive than H&E-staining, revealing significant differences in eosinophil patterns, comparing inflammatory and stricturing pediatric CD. A significant relationship between ileal-eosinophilia and complicated clinical/histopathological phenotype including fibrosis was determined. IL-33 induced significant eosinophil EPX-secretion and IL-13 production. Exposure to eosinophils in the presence of IL-33, ‘primed’ fibroblasts to increase pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), eosinophil-associated chemokines (CCL24, CCL26) and IL-13Rα2 production. Production of fibrogenic molecules (collagen 1A2, fibronectin and periostin) increased following exposure of ‘primed’-fibroblasts to IL-13. Epithelial-IL-33 was increased in pediatric Crohn’s-ileitis and strongly associated with clinical and histopathological activity, ileal eosinophilia and complicated, fibrostenotic disease. SAMP1/SkuSlc eosinophil-targeted treatment resulted in significant improvements in inflammation and remodeling. Conclusions Our study of specimens from pediatric patients with ileal CD linked eosinophil patterns and IL-33 to fibrosis; and suggested these may contribute to the perpetuation of inflammation and subsequent stricture in pediatric CD.

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Section: Discussionmentioning

confidence: 71%

Eosinophils and IL-33 Perpetuate Chronic Inflammation and Fibrosis in a Pediatric Population with Stricturing Crohnʼs Ileitis

Masterson

Capocelli

Hosford

et al. 2015

Inflammatory Bowel Diseases

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“…CCR3 interacts with CCL5 (RANTES), CCL7 (MCP-3), CCL11 (eotaxin-1), CCL13 (MCP-4), CCL24 (eotaxin-2), and CCL26 (eotaxin-3) [26][27][28][29]. CCR3 shows the maximal binding affinity for CCL11 (K d of 0.1 nM) compared with the other ligands [26].…”

Section: Ccr3 and Its Ligand Ccl11mentioning

confidence: 99%

“…These molecules are important mediators of colon inflammation [33][34][35]. Eotaxin-3 (CCL26) expression is reported in the active lesions of UC and CD patients, and it also promotes the recruitment of eosinophils in the gut [28]. Furthermore, eosinophilic esophagitis, an allergic inflammatory condition of the esophagus, is characterized by eosinophilic infiltration.…”

Section: Ccr3 and Its Ligand Ccl11mentioning

confidence: 99%

Role of chemokine receptors and intestinal epithelial cells in the mucosal inflammation and tolerance

Kulkarni

Pathak

Lal

2016

Journal of Leukocyte Biology

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The intestinal epithelial lining is a very dynamic interface, where multiple interactions occur with the external world. The intestinal epithelial barrier is continuously exposed to a huge load of commensal microorganisms, food-borne antigens, as well as invading enteropathogens. Intestinal epithelial cells (IECs) and underlying immune cells are the main players in maintaining the delicate balance between gut tolerance and inflammation. IECs deferentially express the variety of chemokines and chemokine receptors, and these receptor-ligand interactions not only mediate the infiltration and activation of immune cells but also switch on the survival cascades in IECs. In this review, we discussed how chemokine-chemokine receptor-induced interactions play a central role to coordinate the interplay between IECs and gut immune cells to maintain homeostasis or elicit gut inflammation. Furthermore, we discussed how chemokines and chemokine receptors were used as a target for developing new drugs and therapies to control gut inflammation and autoimmunity.

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“…4,20 By elevating expression of the tight junction paracellular pore component, claudin-2, IL-13 may also promote ion flux across the barrier. 21,22 In parasite infection models, both IL-4 and IL-13 have been found to influence goblet cell hyperplasia, [23][24][25] eotaxin expression in colonic mucosa 26 and smooth muscle hypercontractility 27,28 in the gut. Interleukin-13 is a potent inducer of tissue fibrosis, 29 has been associated with fibrotic changes in fistulas of inflammatory bowel disease (IBD), 30 and represents a promising therapeutic target for the treatment of colitis.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic activity of an interleukin‐4/interleukin‐13 dual antagonist on oxazolone‐induced colitis in mice

et al. 2014

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SummaryInterleukin-4 (IL-4) and IL-13 are critical drivers of immune activation and inflammation in ulcerative colitis, asthma and other diseases. Because these cytokines may have redundant function, dual targeting holds promise for achieving greater efficacy. We have recently described a bifunctional therapeutic targeting IL-4 and IL-13 developed on a novel protein scaffold, generated by combining specific binding domains in an optimal configuration using appropriate linker regions. In the current study, the bifunctional IL-4/IL-13 antagonist was evaluated in the murine oxazoloneinduced colitis model, which produces disease with features of ulcerative colitis. The bifunctional IL-4/IL-13 antagonist reduced body weight loss throughout the 7-day course of the model, and ameliorated the increased colon weight and decreased colon length that accompany disease. Colon tissue gene expression was modulated in accordance with the treatment effect. Concentrations of serum amyloid P were elevated in proportion to disease severity, making it an effective biomarker. Serum concentrations of the bifunctional IL-4/IL-13 antagonist were inversely proportional to disease severity, colon tissue expression of pro-inflammatory genes, and serum amyloid P concentration. Taken together, these results define a panel of biomarkers signifying engagement of the IL-4/IL-13 pathway, confirm the T helper type 2 nature of disease in this model, and demonstrate the effectiveness of dual cytokine blockade.

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Regulation of eotaxin-3/CC chemokine ligand 26 expression by T helper type 2 cytokines in human colonic myofibroblasts

Cited by 25 publications

References 35 publications

Eosinophils and IL-33 Perpetuate Chronic Inflammation and Fibrosis in a Pediatric Population with Stricturing Crohnʼs Ileitis

Eosinophils and IL-33 Perpetuate Chronic Inflammation and Fibrosis in a Pediatric Population with Stricturing Crohnʼs Ileitis

Role of chemokine receptors and intestinal epithelial cells in the mucosal inflammation and tolerance

Therapeutic activity of an interleukin‐4/interleukin‐13 dual antagonist on oxazolone‐induced colitis in mice

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