Early bacterial dependent induction of inducible nitric oxide synthase (iNOS) in epithelial cells upon transfer of CD45RB(high) CD4(+) T cells in a model for experimental colitis.
BACKGROUND
Both the role of inducible nitric oxide synthase (iNOS) in the development of inflammatory bowel disease (IBD) as well as the molecular details governing its mucosal induction remain unclear.


METHODS
In the present study we evaluated the role of the residing intestinal microflora in the induction of epithelial iNOS upon transfer of CD45RB(high) CD4(+) T cells to SCID mice. CB-17 SCID mice were reared with conventional flora (CNV) or germfree CB-17 SCID mice were monoassociated with Helicobacter muridarum, act A(-) mutant Listeria monocytogenes, segmented filamentous bacteria (SFB), or Ochrobactrum anthropi.


RESULTS
Within 2 weeks CNV SCID mice injected with CD45RB(high) CD4(+) T cells showed a focal, epithelial iNOS expression on the apical site of villi that preceded the infiltration of CD4(+) T cells and cytokine production followed by extension of this expression to the entire surface along the whole crypt axis as the colitis progressed. SCID mice monoassociated with H. muridarum developed a severe colitis and showed high epithelial iNOS expression. CNV-SCID mice without T cells and SCID mice monoassociated with SFB did not show any iNOS expression, whereas SCID mice monoassociated with act A(-) mutant L. monocytogenes and O. anthropi showed some scattered epithelial iNOS staining on the apical site of a few villi, but none of these mice developed colitis.


CONCLUSIONS
These findings demonstrate that the expression of epithelial iNOS is highly bacterium-specific and correlates with the severity of disease, suggesting an important role for this enzyme in the development of IBD.
Dijkstra
Gerard
G
Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, The Netherlands.
Yuvaraj
Saravanan
S
Jiang
Han-Qing
HQ
Bun
Judy C A M
JC
Moshage
Han
H
Kushnir
Natasha
N
Peppelenbosch
Maikel P
MP
Cebra
John J
JJ
Bos
Nicolaas A
NA
D019264:Adoptive Transfer; D000818:Animals; D001419:Bacteria / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D003092:Colitis / Q000473:pathology*; D003106:Colon / Q000473:pathology; D005856:Germ-Free Life; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D051379:Mice; D016513:Mice, SCID; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*
D052247:Nitric Oxide Synthase Type II; D017493:Leukocyte Common Antigens