Mucosal IL-10 and TGF-β play crucial roles in preventing LPS-driven, IFN-γ–mediated epithelial damage in human colon explants

Abstract

IL-10 is an immunomodulatory cytokine that plays an obligate role in preventing spontaneous enterocolitis in mice. However, little is known about IL-10 function in the human intestinal mucosa. We showed here that IL-10 was constitutively expressed and secreted by the human normal colonic mucosa, including epithelial cells. Depletion of IL-10 in mucosal explants induced both downregulation of the IL-10-inducible, immunosuppressive gene BCL3 and upregulation of IFN-γ, TNF-α, and IL-17. Interestingly, TGF-β blockade also strongly induced IFN-γ production. In addition, the high levels of IFN-γ produced upon IL-10 depletion were responsible for surface epithelium damage and crypt loss, mainly by apoptosis. Polymyxin B, used as a scavenger of endogenous LPS, abolished both IFN-γ production and epithelial barrier disruption. Finally, adding a commensal bacteria strain to mucosa explant cultures depleted of both IL-10 and LPS reproduced the ability of endogenous LPS to induce IFN-γ secretion. These findings demonstrate that IL-10 ablation leads to an endogenous IFN-γ-mediated inflammatory response via LPS from commensal bacteria in the human colonic mucosa. We also found that both IL-10 and TGF-β play crucial roles in maintaining human colonic mucosa homeostasis.

Innate Transcriptional Networks Activated in Bladder in Response to Uropathogenic Escherichia coli Drive Diverse Biological Pathways and Rapid Synthesis of IL-10 for Defense against Bacterial Urinary Tract Infection

“…In our study, patients with UPEC cystitis secreted significant urinary IL-10 and produced high levels of IL-10 systemically during UPEC urosepsis. Whether the systemic IL-10 present in patients with UPEC urosepsis has coordinated effects in immune regulation, as described in other clinical conditions, is unknown (66). However, our studies in mice point to the fact that IL-10 produced in the bladder plays a functional role early in UTI disease pathogenesis.…”

“…IL-10R is present on the surface of a variety of other human lymphoid and myeloid cells (85) and is upregulated during infection-induced inflammatory conditions such as sepsis (86). Moreover, human epithelial cells lining the colonic mucosa express IL-10 to control inflammation and maintain mucosal homeostasis (66). It is important to note, however, that our findings on IL-10R transcripts were not extended to detection of the receptor protein, which is a limitation of the current work.…”

Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

“…The source of the anti-inflammatory cytokine IL-10 is widespread and unrelated to a single cell type. In response to a noxious stimulus, at the intestinal level, IL-10 might be directly synthesized by epithelial gut cells, 31 but the prevailing concept in the literature is that IL-10 is synthesized, mainly by immune cells, including regulatory T cells, B cells, macrophages, and dendritic cells. 32,33 Further studies are needed, aimed to identify the immunological players involved and to investigate on the mechanism triggered by D-glucose administration, leading to IL-10 production.…”

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…Gradual and age-dependent maturation of the immune system fulfills several demands, such as preparing the skin and intestine for colonization by commensal bacteria, tolerizing the host for exposure to food and environmental antigens, and protecting against pathogenic infections (PrabhuDas et al 2011). TGF-b preserves the intestinal barrier function (Planchon et al 1994(Planchon et al , 1999Jarry et al 2008), and its production in the intestine is age-dependent (Zhang et al 1999a;Maheshwari et al 2011). For example, rodent pups initially produce low levels of endogenous intestinal TGF-b, which increase during the weaning period (Penttila et al 1998).…”