title: IL-10 modulates DSS-induced colitis through a macrophage-ROS-NO axis.
abstract: Breakdown of the epithelial barrier because of toxins or other insults leads to severe colitis. Interleukin-10 (IL-10) is a critical regulator of this, yet its cellular targets and mechanisms of action are not resolved. We address this here. Mice with a macrophage-selective deletion of IL-10Rα (IL-10Rα(Mdel)) developed markedly enhanced dextran sodium sulfate (DSS)-induced colitis that did not significantly differ from disease in IL-10(-/-) or IL-10Rα(-/-) mice; no impact of IL-10Rα deficiency in other lineages was observed. IL-10Rα(Mdel) colitis was associated with increased mucosal barrier disruption in the setting of intact epithelial regeneration. Lamina propria macrophages (LPMφs) did not show numerical or phenotypic differences from controls, or a competitive advantage over wild-type cells. Proinflammatory cytokine production, and particularly tumor necrosis factor-α (TNF-α), was increased, although TNF-α neutralization failed to reveal a defining role for this cytokine in the aggravated disease. Rather, IL-10Rα(Mdel) LPMφs produced substantially greater levels of nitric oxide (NO) and reactive oxygen species (ROS) than controls. Inhibition of these had modest effects in wild-type mice, although they dramatically reduced colitis severity in IL-10Rα(Mdel) mice, and largely eliminated the differential effect of DSS in them. Therefore, the palliative actions of IL-10 in DSS-induced colitis predominantly results from its macrophage-specific effects. Downregulation of NO and ROS production are central to the protective actions of IL-10.
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: R
authors.initials: R
authors.lastname: Alli
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: P
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Geiger
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D015870:Gene Expression; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D053709:Interleukin-10 Receptor alpha Subunit; D017382:Reactive Oxygen Species; D016753:Interleukin-10; D009569:Nitric Oxide; D016264:Dextran Sulfate