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

PEREZ FEDERICO; SANTIAGO BRAYER; MARTÍN YANTORNO; THOMAS T. MACDONALD ; CURCIARELLO RENATA; KAREN DUBOIS CAMACHO; GUSTAVO CORREA; MARCELA HERMOSO RAMELLO; SOL ROLDAN A; ALICIA SAMBUELLI; FERNANDO CHIRDO; GUILLERMO H. DOCENA

Cancun

Congreso; XII Congress of the Latin American Association of Immunology; 2018

ALAI

Inflammatory bowel diseases (IBD), mainly Crohn's disease (CD) and ulcerative colitis (UC), are chronic intestinal disorders caused by environmental and genetic factors. The gut-associated immune system is permanently activated in these patients, leading to an increase of pro-inflammatory cytokines, which mediate immune cell activation/proliferation and the extracellular matrix remodeling process that cause the intestinal lesions(abscesses, fistulae, fibrosis and stenosis). Even though it is widely known that cytokines are involved in the fibrotic process, there is no current anti-inflammatory therapy able to modulate or reverse fibrosis.Th17 cells and IL-17 are abundantly found in the inflamed intestinal mucosa. Although IL-17A has been reported as a mediator of IBD, the exact role for IL-17 in IBD remains controversial. We have previously shown that IL-17 dimmers (IL-17AA, FF and AF) are differentially produced by UC and CD lamina propria cells, and the anti-inflammatory properties of IL-17AA. On the other hand, IL-33 and its putative receptor ST2 are increased in inflamed mucosa from UC patients and in a lesser extent, from CD patients. Activated intestinal myofibroblasts underlying the ulcerative lesions in UC, but not in CD, secrete IL-33, supporting a functional role for IL-33 in ulceration and wound healing in UC.In order to identify target cells for IL-17 in IBD intestinal mucosa, we aimed to study the effect of IL-17A, IL-17F and IL-17A/F on human colonic myofibroblasts, which may have a pro- or anti-inflammatory role. Moreover, we investigated the modulation of the IL-33/ST2 axis by IL-17.We found that myofibroblasts isolated from intestinal biopsies or surgical samples from IBD adult patients (UC n=3, CD n=4) and healthy donors (HC n=1) when stimulated with recombinant human IL-17A, IL-17F or IL-17AF (1ng/ml), in combination with TNF (1ng/ml) or medium, as control, for 24 hours secreted IL-6 and IL-8 (ELISA). In addition, we found increased expression of IL-33 and ST2 (qPCR and confocal microscopy).When isolated myofibroblasts were stimulated with IL-17 dimmers we could not induce IL-6 or IL-8 secretion, however only IL-17A combined with TNF diminished IL-6 and IL-8 production by UC and CD myofibroblasts compared with TNF alone (p