14 research outputs found
Cytomegalovirus viral load in the colon and risk of colectomy in hospitalized patients with inflammatory bowel diseases
To the Editor:
We read with interest the article of
Lee et al1 describing the risk factors for
adverse outcomes in hospitalized patients
with ulcerative colitis (UC) with concurrent
cytomegalovirus (CMV) colitis.
CMV reactivation and resolution can be
spontaneous in patients with UC regardless
of antiviral therapy; however, inconsistencies
between CMV detection
methods of various studies and criteria
for defining CMV positivity may be leading
to these disparate findings.2,3 In the
study by Lee et al, CMV colitis
was defined by the presence of 1 or more
inclusion bodies on hematoxylin and
eosin staining or CMV immunohistochemistry
on colonic biopsies. The most
accurate approach for detection of clinically
significant CMV infection has not
been firmly established and guidelines differ
in their recommendations.3,4 A recent
study using quantitative colonic PCR in
consecutive patients with UC undergoing
endoscopy in the setting of a moderate to
severe flare demonstrated a correlation
between higher viral load and resistance
to immunosuppressive therapy with significant
differences found when using
a cutoff viral load of .250 per milligram
tissue.
An Anti-Inflammatory Role for Carbon Monoxide and Heme Oxygenase-1 in Chronic Th2-Mediated Murine Colitis
Cigarette smoking is a significant environmental factor in the human inflammatory bowel diseases, remarkably, conferring protection in ulcerative colitis. We previously demonstrated that a prominent component of cigarette smoke, CO, suppresses Th17-mediated experimental colitis in IL-10−/− mice through a heme oxygenase (HO)-1–dependent pathway. In this study, homeostatic and therapeutic effects of CO and HO-1 were determined in chronic colonic inflammation in TCR-α–deficient (−/−) mice, in which colitis is mediated by Th2 cytokines, similar to the cytokine milieu described in human ulcerative colitis. TCRα−/− mice exposed to CO or treated with the pharmacologic HO-1 inducer cobalt protoporphyrin demonstrated amelioration of active colitis. CO and cobalt protoporphyrin suppressed colonic IL-1β, TNF, and IL-4 production, whereas IL-10 protein secretion was increased. CO induced IL-10 expression in macrophages and in vivo through an HO-1–dependent pathway. Bacterial products regulate HO-1 expression in macrophages through MyD88- and IL-10–dependent pathways. CO exposure and pharmacologic HO-1 induction in vivo resulted in increased expression of HO-1 and IL-10 in CD11b+ lamina propria mononuclear cells. Moreover, induction of the IL-10 family member IL-22 was demonstrated in CD11b− lamina propria mononuclear cells. In conclusion, CO and HO-1 induction ameliorated active colitis in TCRα−/− mice, and therapeutic effects correlated with induction of IL-10. This study provides further evidence that HO-1 mediates an important homeostatic pathway with pleiotropic anti-inflammatory effects in different experimental models of colitis and that targeting HO-1, therefore, is a potential therapeutic strategy in human inflammatory bowel diseases
Escherichia coli heme oxygenase modulates host innate immune responses: Bacteria modulate the immune response
Induction of mammalian heme oxygenase-1 and exposure of animals to carbon monoxide ameliorates experimental colitis. When enteric bacteria, including Escherichia coli, are exposed to low iron conditions, they express an heme oxygenase-like enzyme, chuS, and metabolize heme into iron, biliverdin and carbon monoxide. Given the abundance of enteric bacteria residing in the intestinal lumen, we hypothesized that commensal intestinal bacteria may be a significant source of carbon monoxide, with the consequence that enteric bacteria expressing chuS and other heme oxygenase -like molecules suppress inflammatory immune responses through release of carbon monoxide. Carbon monoxide exposed mice have altered enteric bacterial composition and increased E. coli 16S and chuS DNA by real-time PCR. Moreover, severity of experimental colitis correlates with increased E. coli chuS expression in IL-10 deficient mice. To explore functional roles, E. coli were genetically modified to overexpress chuS or the chuS gene was deleted. Co-culture of chuS-overexpressing E. coli with bone marrow derived macrophages results in decreased IL-12 p40 and increased IL-10 secretion compared to wild-type or chuS-deficient E. coli. Mice infected with chuS-overexpressing E. coli have increased levels of hepatic carbon monoxide and decreased serum IL-12 p40 compared to mice infected with chuS-deficient E. coli. Thus, carbon monoxide alters the composition of the commensal intestinal microbiota and expands E. coli populations harboring the chuS gene. These bacteria are capable of attenuating innate immune responses through expression of chuS. Bacterial heme oxygenase -like molecules and bacterial-derived carbon monoxide may represent novel targets for therapeutic intervention in inflammatory conditions
Carbon Monoxide and Heme Oxygenase-1 Prevent Intestinal Inflammation in Mice by Promoting Bacterial Clearance
Heme oxygenase-1 (HO-1) and its metabolic by-product, carbon monoxide (CO), protect against intestinal inflammation in experimental models of colitis, but little is known about their intestinal immune mechanisms. We investigated the interactions among CO, HO-1, and the enteric microbiota in mice and zebrafish
Su1386 Is the Cytomegalovirus (CMV) Viral Load in Colonic Biopsies Associated With a Higher Risk of Colectomy in Hospitalized Patients With Inflammatory Bowel Diseases (IBD)?
An anti-inflammatory role for carbon monoxide and heme oxygenase-1 in chronic Th2-mediated murine colitis
Cigarette smoking is a significant environmental factor in the human inflammatory bowel diseases, remarkably, conferring protection in ulcerative colitis. We previously demonstrated that a prominent component of cigarette smoke, CO, suppresses Th17-mediated experimental colitis in IL-10-/- mice through a heme oxygenase (HO)-1-dependent pathway. In this study, homeostatic and therapeutic effects of CO and HO-1 were determined in chronic colonic inflammation in TCR-α-deficient (-/-) mice, in which colitis is mediated by Th2 cytokines, similar to the cytokine milieu described in human ulcerative colitis. TCRα-/- mice exposed to CO or treated with the pharmacologic HO-1 inducer cobalt protoporphyrin demonstrated amelioration of active colitis. CO and cobalt protoporphyrin suppressed colonic IL-1β, TNF, and IL-4 production, whereas IL-10 protein secretion was increased. CO induced IL-10 expression in macrophages and in vivo through an HO-1-dependent pathway. Bacterial products regulate HO-1 expression in macrophages through MyD88- and IL-10-dependent pathways. CO exposure and pharmacologic HO-1 induction in vivo resulted in increased expression of HO-1 and IL-10 in CD11b+ lamina propria mononuclear cells. Moreover, induction of the IL-10 family member IL-22 was demonstrated in CD11b- lamina propria mononuclear cells. In conclusion, CO and HO-1 induction ameliorated active colitis in TCRβ-/- mice, and therapeutic effects correlated with induction of IL-10. This study provides further evidence that HO-1 mediates an important homeostatic pathway with pleiotropic anti-inflammatory effects in different experimental models of colitis and that targeting HO-1, therefore, is a potential therapeutic strategy in human inflammatory bowel diseases. Copyright © 2011 by The American Association of Immunologists, Inc
514 Heme Oxygenase-1 Maintains Intestinal Homeostasis Through Augmented Enteric Bacterial Clearance
Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor–Dependent Repression of Claudin-2
An Anti-Inflammatory Role for Carbon Monoxide and Heme Oxygenase-1 in Chronic Th2-Mediated Murine Colitis
Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter*
We have demonstrated previously that IFN-γ plays a protective role in the initiation of chronic intestinal inflammation through attenuation of Toll-like receptor-mediated IL-23 induction in macrophages. Here, an interferon-stimulated response element (ISRE) is identified in a region of conserved nucleotide sequences in the Il23a promoter. This ISRE mediated, in part, Il23a promoter induction by LPS and inhibition of LPS-induced activity by IFN-γ. LPS and IFN-γ recruit interferon regulatory factors (IRFs) to the Il23a ISRE in murine bone marrow-derived macrophages (BMMs). Functionally, IRF-1 is a negative regulator of Il23a in LPS-stimulated BMMs. IRF-1−/− BMMs demonstrated enhanced LPS-induced Il23a expression compared with WT BMMs. Moreover, IRF-1 deficiency resulted in prolonged occupancy of RelA on the Il23a promoter. Consequently, IRF-1−/− mice were more susceptible to colonic injury by trinitrobenzenesulfonic acid, and IL-10/IRF-1 double-deficient (IL-10/IRF-1−/−) mice demonstrated more severe colonic inflammation compared with IL-10−/− mice. The severity of colitis in both models correlated with increased colonic IL-23. CD11b+ lamina propria mononuclear cells, comprising predominantly macrophages, were identified as the major source of IL-23 in colitis-prone mice. Basal and heat-killed Escherichia coli-stimulated levels of Il23a were increased in IL-10/IRF-1−/− compared with WT and IL-10−/− colonic CD11b+ lamina propria mononuclear cells. In conclusion, these experiments characterize IRF-ISRE interactions on the Il23a promoter, which have in vivo relevance as a homeostatic checkpoint in chronic intestinal inflammation