Although intestinal epithelial cells appear to be functionally
hyporesponsive to normal intestinal flora, human intestinal epithelial cells
can respond to enteroinvasive bacteria and induce an ...inflammatory response.
This initial inflammatory response leads to the recruitment of
polymorphonuclear leukocytes to the affected site in vitro and in
vivo . CARD4/NOD1 is a potential cytosolic receptor for peptidoglycan in
mammalian cells that resembles pathogen-resistant proteins of plants. In this
context, CARD4/NOD1 is a candidate for a recognition protein of intracellular
bacteria or peptidoglycan in intestinal epithelial cells. In this study, we
demonstrate that CARD4/NOD1 is constitutively expressed in intestinal
epithelial cell lines and isolated primary intestinal epithelial cells.
Interferon-γ (IFNγ), which is a potent pro-inflammatory cytokine
in intestinal mucosal inflammation, activates CARD4/NOD1 mRNA transcription in
a time- and dose-dependent manner and results in augmentation of CARD4/NOD1
protein in SW480 cells. Promoter analysis of CARD4/NOD1 indicates that
interferon regulatory factor-1 (IRF-1) binding motif (â791 to
â782) is essential for the effect of IFNγ. Nuclear extracts from
SW480 cells treated with IFNγ show specific binding of oligonucleotides
corresponding to this IRF-1-binding motif, which was supershifted by
anti-IRF-1 antibody in electrophoretic mobility shift assay. Overexpression of
IRF-1 protein activates the CARD4/NOD1 promoter but not the deletion mutant of
the IRF-1-binding site in a co-transfection assay of IRF-1 expression plasmid
with CARD4/NOD1 promoter. These studies suggest that the Th1 cytokine,
IFNγ, activates CARD4/NOD1 transcription and regulate innate immune
mechanisms in the condition of intestinal mucosal inflammation.
Ulcerative colitis (UC) has been known as inflammatory bowel disease. Progress in UC management strategies has led to optimized approaches for achieving the two primary clinical goals of therapy: ...induction and maintenance of remission. We here review about immunosuppressants in management of UC; Cyclosporine A (CsA) has been used for the induction therapy in steroid resistant refractory UC. Although it has been reported that CsA has high response rate in severe UC, long-term efficacy (maintenance of remission) has not been proven. To improve maintenance therapy, immunosuppressant has been re-considered in management of UC. In recent years, it has been reported that efficacy of 6-mercaptopurine/azathioprine in maintenance of remission of UC is superior to 5-aminosalicylate (5-ASA). Pharmacological studies have indicated thiopurine methyltransferase (TPMT) activity is essential for maintenance of blood concentration of 6-thioguanine nucleotide (6-TG).
The liver is a physiological site of immune tolerance, the breakdown of which induces immunity. Liver antigen-presenting cells may be involved in both immune tolerance and activation. Although ...inflammatory diseases of the liver are frequently associated with inflammatory bowel diseases, the underlying immunological mechanisms remain to be elucidated. Here we report two murine models of inflammatory bowel disease: RAG-2-/- mice adoptively transferred with CD4+CD45RBhigh T cells; and IL-10-/- mice, accompanied by the infiltration of mononuclear cells in the liver. Notably, CD11b-CD11clowPDCA-1+ plasmacytoid dendritic cells (DCs) abundantly residing in the liver of normal wild-type mice disappeared in colitic CD4+CD45RBhigh T cell-transferred RAG-2-/- mice and IL-10-/- mice in parallel with the emergence of macrophages (M phi s) and conventional DCs (cDCs). Furthermore, liver M phi /cDCs emerging during intestinal inflammation not only promote the proliferation of naive CD4+ T cells, but also instruct them to differentiate into IFN- gamma -producing Th1 cells in vitro. The emergence of pathological M phi /cDCs in the liver also occurred in a model of acute dextran sulfate sodium (DSS)-induced colitis under specific pathogen-free conditions, but was canceled in germ-free conditions. Last, the M phi /cDCs that emerged in acute DSS colitis significantly exacerbated Fas-mediated hepatitis. Collectively, intestinal inflammation skews the composition of antigen-presenting cells in the liver through signaling from commensal bacteria and predisposes the liver to inflammation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Centaurin beta1 (CENTB1), a GTPase-activating protein, is a member of the ADP-ribosylation factor family encoded by a gene located on the short arm of human chromosome 17. A yeast two-hybrid screen ...first suggested a direct interaction between CENTB1 and NOD2. Co-immunoprecipitation experiments confirmed direct interaction between CENTB1 and NOD2 and demonstrated similar interaction between CENTB1 and NOD1. We also demonstrate that endogenous CENTB1 interacts with endogenous NOD2 and NOD1 in SW480 and HT-29 intestinal epithelial cells. CENTB1 partially co-localized with NOD2 and NOD1 proteins in the cytoplasm of mammalian cells. CENTB1 expression in epithelial cells was highly induced by tumor necrosis factor alpha, interleukin 1beta, and the NOD1 and NOD2 ligands (gamma-d-glutamyl-meso-diaminopimelic acid and muramyl dipeptide, respectively). In addition, CENTB1 mRNA level is increased in the inflamed mucosa of patients with inflammatory bowel disease. Functionally, CENTB1 overexpression inhibited NOD1- and NOD2-dependent activation of NF-kappaB, whereas small inhibitory RNA against CENTB1 increased NF-kappaB activation following NOD1- or NOD2-mediated recognition of the bacterial components gamma-d-glutamyl-meso-diaminopimelic acid and muramyl dipeptide, respectively. In contrast, CENTB1 had no effect on NF-kappaB activation induced by Toll-like receptors. In conclusion, CENTB1 selectively down-regulates NF-kappaB activation via NODs pathways, creating a "feedback" loop and suggesting a novel role of CENTB1 in innate immune responses to bacteria and inflammatory responses.
Centaurin β1 (CENTB1), a GTPase-activating protein, is a member of the ADP-ribosylation factor family encoded by a gene located
on the short arm of human chromosome 17. A yeast two-hybrid screen ...first suggested a direct interaction between CENTB1 and
NOD2. Co-immunoprecipitation experiments confirmed direct interaction between CENTB1 and NOD2 and demonstrated similar interaction
between CENTB1 and NOD1. We also demonstrate that endogenous CENTB1 interacts with endogenous NOD2 and NOD1 in SW480 and HT-29
intestinal epithelial cells. CENTB1 partially co-localized with NOD2 and NOD1 proteins in the cytoplasm of mammalian cells.
CENTB1 expression in epithelial cells was highly induced by tumor necrosis factor α, interleukin 1β, and the NOD1 and NOD2
ligands (γ- d -glutamyl-meso-diaminopimelic acid and muramyl dipeptide, respectively). In addition, CENTB1 mRNA level is increased in the
inflamed mucosa of patients with inflammatory bowel disease. Functionally, CENTB1 overexpression inhibited NOD1- and NOD2-dependent
activation of NF-κB, whereas small inhibitory RNA against CENTB1 increased NF-κB activation following NOD1- or NOD2-mediated
recognition of the bacterial components γ- d -glutamyl-meso-diaminopimelic acid and muramyl dipeptide, respectively. In contrast, CENTB1 had no effect on NF-κB activation
induced by Toll-like receptors. In conclusion, CENTB1 selectively down-regulates NF-κB activation via NODs pathways, creating
a âfeedbackâ loop and suggesting a novel role of CENTB1 in innate immune responses to bacteria and inflammatory responses.
Intestinal macrophages play a central role in regulation of immune responses against commensal bacteria. In general, intestinal macrophages lack the expression of innate-immune receptor CD14 and do ...not produce proinflammatory cytokines against commensal bacteria. In this study, we identified what we believe to be a unique macrophage subset in human intestine. This subset expressed both macrophage (CD14, CD33, CD68) and DC markers (CD205, CD209) and produced larger amounts of proinflammatory cytokines, such as IL-23, TNF-alpha, and IL-6, than typical intestinal resident macrophages (CD14-CD33+ macrophages). In patients with Crohn disease (CD), the number of these CD14+ macrophages were significantly increased compared with normal control subjects. In addition to increased numbers of cells, these cells also produced larger amounts of IL-23 and TNF-alpha compared with those in normal controls or patients with ulcerative colitis. In addition, the CD14+ macrophages contributed to IFN-gamma production rather than IL-17 production by lamina propria mononuclear cells (LPMCs) dependent on IL-23 and TNF-alpha. Furthermore, the IFN-gamma produced by LPMCs triggered further abnormal macrophage differentiation with an IL-23-hyperproducing phenotype. Collectively, these data suggest that this IL-23/IFN-gamma-positive feedback loop induced by abnormal intestinal macrophages contributes to the pathogenesis of chronic intestinal inflammation in patients with CD.
Intestinal macrophages play a central role in regulation of immune responses against commensal bacteria. In general, intestinal macrophages lack the expression of innate-immune receptor CD14 and do ...not produce proinflammatory cytokines against commensal bacteria. In this study, we identified what we believe to be a unique macrophage subset in human intestine. This subset expressed both macrophage (CD14, CD33, CD68) and DC markers (CD205, CD209) and produced larger amounts of proinflammatory cytokines, such as IL-23, TNF-α, and IL-6, than typical intestinal resident macrophages (CD14.sup.-CD33.sup.+ macrophages). In patients with Crohn disease (CD), the number of these CD14.sup.+ macrophages were significantly increased compared with normal control subjects. In addition to increased numbers of cells, these cells also produced larger amounts of IL-23 and TNF-α compared with those in normal controls or patients with ulcerative colitis. In addition, the CD14.sup.+ macrophages contributed to IFN-γ production rather than IL-17 production by lamina propria mononuclear cells (LPMCs) dependent on IL-23 and TNF-α. Furthermore, the IFN-γ produced by LPMCs triggered further abnormal macrophage differentiation with an IL-23-hyperproducing phenotype. Collectively, these data suggest that this IL-23/IFN-γ--positive feedback loop induced by abnormal intestinal macrophages contributes to the pathogenesis of chronic intestinal inflammation in patients with CD.
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