Expression of inducible nitric oxide synthase activity in human colon epithelial cells: modulation by T lymphocyte derived cytokines

Kolios, George; Rooney, N.; Murphy, Christine; Robertson, Douglas R.; Westwick, John

doi:10.1136/gut.43.1.56

Cited by 125 publications

(107 citation statements)

References 51 publications

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“…Because (28), epithelial-derived NO may also function in an antimicrobial role against enteric bacteria. This hypothesis is supported by studies in which enteroinvasive bacteria induce iNOS expression by cultured epithelial cells (59), similar to the effects of several proinflammatory cytokines (28). Moreover, we recently demonstrated that iNOS is strongly induced on colonic epithelial cells in mice infected with the gram-negative bacterial pathogen Citrobacter rodentium, a mouse-adapted version of enteropathogenic Escherichia coli.…”

Section: Discussionsupporting

confidence: 55%

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Vallance¹,

Dijkstra²,

Qiu³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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The role of nitric oxide (NO) in inflammatory bowel diseases has traditionally focused on the inducible form of NO synthase (iNOS). However, the constitutive endothelial (eNOS) and neuronal (nNOS) isoforms may also impact on colitis, either by contributing to the inflammation or by regulating mucosal integrity in response to noxious stimuli. To date, studies examining the roles of the NOS isoforms in experimental colitis have been conflicting, and the mechanisms by which these enzymes exert their effects remain unclear. To investigate and clarify the roles of the NOS isoforms in gut inflammation, we induced trinitrobenzenesulfonic acid colitis in eNOS, nNOS, and iNOS knockout (KO) mice, assessing the course of colitis at early and late times. Both eNOS and iNOS KO mice developed a more severe colitis compared with wild-type mice. During colitis, iNOS expression dramatically increased on epithelial and lamina propria mononuclear cells, whereas eNOS expression remained localized to endothelial cells. Electron and fluorescence microscopy identified bacteria in the ulcerated colonic mucosa of eNOS KO mice, but not in wild-type, iNOS, or nNOS KO mice. Furthermore, eNOS KO mice had fewer colonic goblet cells, impaired mucin production, and exhibited increased susceptibility to an inflammatory stimulus that was subthreshold to other mice. This susceptibility was reversible, because the NO donor isosorbide dinitrate normalized goblet cell numbers and ameliorated subsequent colitis in eNOS KO mice. These results identify a protective role for both iNOS and eNOS during colitis, with eNOS deficiency resulting in impaired intestinal defense against lumenal bacteria and increased susceptibility to colitis. mucus; bacteria; inflammatory bowel diseases; goblet cells SEVERAL FACTORS HAVE BEEN implicated in the pathogenesis of human inflammatory bowel diseases (IBD) including an immunological intolerance to enteric microflora (10 -12, 43), as well as defects in mucosal barrier function (47). Recently, attention has been focused on the overproduction of nitric oxide (NO) in IBD (7,31,46,58). Several studies have identified increased levels of NO in the rectal dialysates (46), in the inflamed mucosa of patients with ulcerative colitis (UC) (3), and in animal models of colitis (26,37,60). The increased NO synthase (NOS) activity was identified predominantly as the inducible form of NOS (iNOS) (23). Whereas the two constitutive isoforms, neuronal (nNOS) and endothelial-derived (eNOS), modulate several aspects of intestinal physiology (6, 53), their contribution to the inflammatory response has received less attention.Despite considerable evidence that iNOS-derived NO contributes to tissue destruction in colitis and other inflammatory states (27), conflicting results have been obtained by using pharmacological inhibitors of NOS in animal models of IBD. Several studies have found that the nonspecific NOS inhibitor N G -nitro-L-arginine methyl ester reduced intestinal inflammation (17, 37, 45); other studies found little benefit (20) o...

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Section: Discussionsupporting

confidence: 55%

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Vallance¹,

Dijkstra²,

Qiu³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…TNF-␣ is a key inducer of NOS2 expression (20), whereas IL-4 has been shown to inhibit NOS2 induction (21). We therefore examined TNF-␣ and IL-4 mRNA levels in the small intestines of these mice.…”

Section: Resultsmentioning

confidence: 99%

Neuronal Nitric Oxide Synthase Is Necessary for Elimination of Giardia lamblia Infections in Mice

Zhou

Singer

2006

The Journal of Immunology

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NO produced by inducible NO synthase (NOS2) is important for the control of numerous infections. In vitro, NO inhibits replication and differentiation of the intestinal protozoan parasite Giardia lamblia. However, the role of NO against this parasite has not been tested in vivo. IL-6-deficient mice fail to control Giardia infections, and these mice have reduced levels of NOS2 mRNA in the small intestine after infection compared with wild-type mice. However, NOS2 gene-targeted mice and wild-type mice treated with the NOS2 inhibitor N-iminoethyl-l-lysine eliminated parasites as well as control mice. In contrast, neuronal NOS (NOS1)-deficient mice and wild-type mice treated with the nonspecific NOS inhibitor NG-nitro-l-arginine methyl ester and the NOS1-specific inhibitor 7-nitroindazole all had delayed parasite clearance. Finally, Giardia infection increased gastrointestinal motility in wild-type mice, but not in SCID mice. Furthermore, treatment of wild-type mice with NG-nitro-l-arginine methyl ester or loperamide prevented both the increased motility and the elimination of parasites. Together, these data show that NOS1, but not NOS2, is necessary for clearance of Giardia infection. They also suggest that increased gastrointestinal motility contributes to elimination of the parasite and may also contribute to parasite-induced diarrhea. Importantly, this is the first example of NOS1 being involved in the elimination of an infection.

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“…It is well documented that IL-13 inhibits the production of PGES, Cox2, iNOS and cytokines such as IL-1 or TNF-a in fibroblasts or macrophages, but enhances IL-1RA production [12,20,27,[34][35][36]. This study demonstrated that serum containing IL-13-Ig inhibited PGES, Cox2, IL1b, iNOS and TNF-a gene expression in NC cells (mainly fibroblasts, smooth muscle cells, endothelial cells and CD11b + cells) in EAM hearts, while it enhanced the expression of IL-1RA.…”

Section: Effect Of Il-13-ig On Target Cells In Eammentioning

confidence: 99%

The effect of hydrodynamics-based delivery of an IL-13-Ig fusion gene for experimental autoimmune myocarditis in rats and its possible mechanism

et al. 2005

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Interleukin (IL)-13 is a pleiotropic cytokine secreted by activated Th2 T lymphocytes. Th1 cytokines are assumed to exacerbate and Th2 cytokines to ameliorate rat experimental autoimmune myocarditis (EAM). Here, we examined the effect of IL-13 on EAM, using a hydrodynamics-based delivery of an IL-13-Ig fusion gene, as well as the possible mechanism of its effect. Rats were immunized on day 0, and IL-13-Ig-treated rats were injected with pCAGGS-IL-13-Ig, and control rats with pCAGGS-Ig, on day 1 or 7. On day 17, the IL-13-Ig gene therapy was effective in controlling EAM as monitored by a decreased heart weight/body weight ratio, by reduced myocarditis and by reduced atrial natriuretic peptide mRNA in the heart, as a heart failure marker. On the basis of IL-13 receptor mRNA expression in separated cells from EAM hearts, we proposed that IL-13-Ig target cells were CD11b + cells and non-cardiomyocytic noninflammatory (NCNI) cells, such as fibroblasts, smooth muscle or endothelial cells. IL-13-Ig inhibited expression of the genes for prostaglandin E synthase, cyclooxygenase-2, inducible nitric oxide synthase, IL-1b and TNF-a in cultivated cells from EAM hearts, while it enhanced expression of the IL-1 receptor antagonist gene. We conclude that IL-13-Ig ameliorates EAM and suppose that its effectiveness may be due to the influence on these immunologic molecules in CD11b + and NCNI cells.

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Expression of inducible nitric oxide synthase activity in human colon epithelial cells: modulation by T lymphocyte derived cytokines

Cited by 125 publications

References 51 publications

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Neuronal Nitric Oxide Synthase Is Necessary for Elimination of Giardia lamblia Infections in Mice

The effect of hydrodynamics-based delivery of an IL-13-Ig fusion gene for experimental autoimmune myocarditis in rats and its possible mechanism

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