T-cell regulation of neutrophil infiltrate at the early stages of a murine colitis model.
BACKGROUND
T-cells are a main target for antiinflammatory drugs in inflammatory bowel disease. As the innate immune system is also implicated in the pathogenesis of these diseases, T-cell suppressors may not only inhibit T-cell-dependent production of proinflammatory mediators but also affect innate immune cell function. Specifically, these drugs may impair innate immune cell recruitment and activation through inhibition of T-cells or act independent of T-cell modulation. We explored the extent of immune modulation by the T-cell inhibitor tacrolimus in a murine colitis model.


METHODS
We assessed the effects of tacrolimus on trinitro-benzene sulphonic acid (TNBS) colitis in wildtype and Rag2-deficient mice. The severity of colitis was assessed by means of histological scores and weight loss. We further characterized the inflammation using immunohistochemistry and by analysis of isolated intestinal leukocytes at various stages of disease.


RESULTS
Tacrolimus-treated wildtype mice were less sensitive to colitis and had fewer activated T-cells. Inhibition of T-cell function was associated with strongly diminished recruitment of infiltrating neutrophils in the colon at the early stages of this model. In agreement, immunohistochemistry demonstrated that tacrolimus inhibited production of the neutrophil chemoattractants CXCL1 and CXCL2. Rag2-deficient mice displayed an enhanced baseline level of lamina propria neutrophils that was moderately increased in TNBS colitis and remained unaffected by tacrolimus.


CONCLUSIONS
Both the innate and the adaptive mucosal immune system contribute to TNBS colitis. Tacrolimus suppresses colitis directly through inhibition of T-cell activation and by suppression of T-cell-mediated recruitment of neutrophils.
van Lierop
Pieter P E
PP
Department of Pediatrics, Division of Gastroenterology & Nutrition, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
de Haar
Colin
C
Lindenbergh-Kortleve
Dicky J
DJ
Simons-Oosterhuis
Ytje
Y
van Rijt
Leonie S
LS
Lambrecht
Bart N
BN
Escher
Johanna C
JC
Samsom
Janneke N
JN
Nieuwenhuis
Edward E S
EE
D056704:Adaptive Immunity / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects / Q000473:pathology; D004167:Diphtheria Toxin / Q000633:toxicity; D004195:Disease Models, Animal; D018450:Disease Progression; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016559:Tacrolimus / Q000494:pharmacology
D004268:DNA-Binding Proteins; D004167:Diphtheria Toxin; D007166:Immunosuppressive Agents; C499308:Rag2 protein, mouse; D016559:Tacrolimus