IL‐6 promotes immune responses in human ulcerative colitis and induces a skin‐homing phenotype in the dendritic cells and Tcells they stimulate

Abstract

Dendritic cells (DCs) control the type and location of immune responses. Ulcerative colitis (UC) is considered a Th2 disease mediated by IL-13 where up to one third of patients can develop extraintestinal manifestations. Colonic biopsies from inflamed and noninflamed areas of UC patients were cultured in vitro and their supernatants were used to condition human blood enriched DCs from healthy controls. Levels of IL-13 in the culture supernatants were below the detection limit in most cases and the cytokine profile suggested a mixed profile rather than a Th2 cytokine profile. IL-6 was the predominant cytokine found in inflamed areas from UC patients and its concentration correlated with the Mayo endoscopic score for severity of disease. DCs conditioned with noninflamed culture supernatants acquired a regulatory phenotype with decreased stimulatory capacity. However, DCs conditioned with inflamed culture supernatants acquired a proinflammatory phenotype with increased expression of the skin-homing chemokine CCR8. These DCs did not have decreased T-cell stimulatory capacity and primed T cells with the skin-homing CLA molecule in an IL-6-dependent mechanism. Our results highlight the role of IL-6 in UC and question the concept of UC as a Th2 disease and the relevance of IL-13 in its etiology.Keywords: Dendritic cells r IL-6 r Mucosal immunity r Intestinal immunity r Ulcerative colitis Correspondence: Prof. Stella C. Knight e-mail: s.knight@imperial.ac.uk IntroductionThe gastrointestinal tract is in contact with a wide variety of commensal microbiota and diverse pathogens, and therefore C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 1338 David Bernardo et al. Eur. J. Immunol. 2012. 42: 1337-1353 requires a balance to be maintained between immunity and immune tolerance; the lack of immune responses against food antigens and/or the commensal microbiota is essential to maintain the homeostasis of the gastrointestinal tract [1]. Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD), traditionally related to a Th2 cytokine profile mediated by 3], where immune homeostasis of the gastrointestinal tract is compromised. Up to 1/3rd of UC patients can develop extraintestinal manifestations with the skin being one of such tissues [4,5].Dendritic cells (DCs) are the most potent antigen presenting cells and determine the nature and type of immune responses [6,7]. Intestinal DCs control immune tolerance in the gastrointestinal tract [8][9][10]. DCs also maintain immune responses localized to specific tissues, since they imprint specific tissue-homing profiles on stimulated T cells [11]. Retinoic acid (RA), the active form of vitamin A following dehydrogenization by the RALDH2 enzyme controls some of the mechanisms of immune homeostasis of the gut [12][13][14]. RA-producing DCs mediate the IgA switching of B cells [15], the generation of T cells with a regulatory phenotype [10], and the imprinting of gut-homing markers on B and T cells [16,17], thereby keeping tolerogenic immune responses com...

Absence of a role for interleukin‐13 in inflammatory bowel disease

“…As an internal control, to ascertain that our detection system was working properly, we measured IL-13 also in the supernatants of LPMCs cultured with exogenous rhIL-13, and indeed its concentration was as expected (data not shown). Our findings are in keeping with the recent study by Bernardo et al [29], who observed nearly no production of IL-13 by both inflamed and uninflamed UC mucosa. These results are further supported by the reduced percentage of IL-13-producing cells, namely NKT cells, which we detected within inflamed mucosa of clinically active UC patients compared with CD patients and control subjects.…”

“…5). The concentrations of IL-13 were uniformly low in all samples (strictured CD ileum: median 24 pg/mL, range 15-30; non-strictured CD ileum: median 19 pg/mL, range 9-28; healthy ileum of control subjects: median 22 pg/mL, range [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Table 1.…”

The Macrophage Migration Inhibitory Factor Homolog of Entamoeba histolytica Binds to and Immunomodulates Host Macrophages

“…IL-6 is a proinflammatory cytokine, and its main sources in the intestine are macrophages. IL-6 plays a crucial role in the uncontrolled inflammation of the intestinal mucosa that is characteristic of IBD (43,44). These findings support the concept that EhMIF might contribute to the immunopathology of intestinal amebiasis.…”

Constitutive gut-homing capacity on circulating myeloid dendritic cells in coeliac disease

“…However, as DC do not recirculate it is difficult to understand how they display altered homing profile trafficking them to the target tissue where the inflammation is ongoing. Indeed, such altered DC homing profile could be a constitutive factor of the disease or on the contrary be consequence of the ongoing gastrointestinal inflammation which has the capacity to modulate -via secreted cytokines-homing profile and homing-imprinting capacity of DC (8). To further our understanding in the mechanisms of the altered DC trafficking in gastrointestinal disease, here we assessed the homing profile of another small bowel condition, CD, focusing on GFD-treated patients.…”