IL-33 AND THE PRO-INFLAMMATORY RESPONSE OF COLONIC FIBROBLASTS FROM PATIENTS WITH INFLAMMATORY BOWEL DISEASE ARE MODULATED BY INTERLEUKIN-17

RENATA CURCIARELLO; FEDERICO PÉREZ; ANA SOL ROLDÁN; KAREN DUBOIS CAMACHO; SANTIAGO BRAYER; ALICIA SAMBUELLI; GUSTAVO J. CORREA; MARTÍN YANTORNO; FERNANDO CHIRDO; MARCELA HERMOSO RAMELLO; THOMAS T. MACDONALD; GUILLERMO HORACIO DOCENA

Cancun

Congreso; XII Congress of the Latin American Association of Immunology & XXIII Congress of the Mexican Society of Immunology; 2018

Asociación Latinoamericana de Inmunología ALAI

Inflammatorybowel diseases (IBD), mainly Crohn's disease (CD) and ulcerativecolitis (UC), are chronic intestinal disorders caused byenvironmental and genetic factors. The gut-associated immune system ispermanently activated in IBD, leading to an increase of pro-inflammatorycytokines, mediating immune cell activation/proliferation and extracellularmatrix remodeling processes that cause the intestinal lesions (abscesses,fistulae, fibrosis and stenosis). Even though it is widely known that cytokines are involved in the fibrotic process, currentlyno anti-inflammatory therapy is available to modulate or reverse fibrosis.Th17 cells and IL-17 are abundantly found in theinflamed intestinal mucosa, although IL-17A has been reported as a mediator ofIBD, its exact role remains unclear. We have previously shown that IL-17dimmers (IL-17AA, FF and AF) are differentially produced by UC and CD laminapropria cells, and even the anti-inflammatory properties of IL-17AA. Additionally,IL-33and its receptor ST2 are increased in inflamed mucosa from UC patients and in alesser extent, from CD patients. We have found that activated intestinalmyofibroblasts trigger the ulcerative lesions in UC, but not in CD, while secretingIL-33, and thus supporting a functional role for IL-33 in ulceration and woundhealing in UC.In order toidentify target cells for IL-17 in IBD intestinal mucosa, we studied the effect of IL-17A,IL-17F and IL-17A/F on the inflammatory response of human colonic myofibroblasts.Additionally, investigations were carriedout on the modulation of the IL-33/ST2 axis by IL-17.Myofibroblasts isolated from intestinal biopsies/surgical samples from adultpatients (UC n=3, CD n=4) and healthy donors (HC n=1) were found to secreteIL-6 and IL-8 (detected by ELISA) when stimulated for 24 hours with recombinanthuman IL-17A, IL-17F or IL-17AF (1ng/ml) (combined with 1ng/ml TNF or medium). Moreover,increased expression of IL-33 and ST2 was detected in myofibroblasts exposed tosimilar conditions (qPCR and confocal microscopy).Further analysis of myofibroblasts stimulated with IL-17 dimmers revealedno secretion of IL-6 or IL-8, however IL-17A+TNF diminished cytokine productioncompared with TNF on its own (p<0.1). Lastly, IL-17 dimmers induced a two-to eight-fold increase in IL-33 and ST2 expression on UC and CD fibroblasts atboth mRNA and protein levels (expression levels were higher in CD fibroblasts frominflamed than uninflamed mucosa from the same patient (p<0.05)). In conclusion, wefound that intestinal myofibroblasts from IBD patients are target cells forIL-17 and IL-17 dimmers differentially modulated the pro-inflammatory response.Moreover, CD fibroblasts expressed IL-33 and ST2, which has been described sofar as exclusively produced by UC fibroblasts. Understanding the role ofcytokines involved in IBD mucosal inflammation may pave the way to identify newtherapeutic targets to prevent or control the IBD-associated fibrosis process.