T helper type 1 memory cells disseminate postoperative ileus over the entire intestinal tract.
Localized abdominal surgery can lead to disruption of motility in the entire gastrointestinal tract (postoperative ileus). Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how the macrophages are activated, especially those in unmanipulated intestinal areas. Here we show that intestinal surgery activates intestinal CD103(+)CD11b(+) dendritic cells (DCs) to produce interleukin-12 (IL-12). This promotes interferon-γ (IFN-γ) secretion by CCR9(+) memory T helper type 1 (T(H)1) cells which activates the macrophages. IL-12 also caused some T(H)1 cells to migrate from surgically manipulated sites through the bloodstream to unmanipulated intestinal areas where they induced ileus. Preventing T cell migration with the drug FTY720 or inhibition of IL-12, T-bet (T(H)1-specific T box transcription factor) or IFN-γ prevented postoperative ileus. CCR9(+) T(H)1 memory cells were detected in the venous blood of subjects 1 h after abdominal surgery. These findings indicate that postoperative ileus is a T(H)1 immune-mediated disease and identify potential targets for disease monitoring and therapy.
Institutes for Molecular Medicine and Experimental Immunology, University Clinic of Bonn, Bonn, Germany.
Daniel R
DR
Engel
Arne
A
Koscielny
Sven
S
Wehner
Juliane
J
Maurer
Marzena
M
Schiwon
Lars
L
Franken
Beatrix
B
Schumak
Andreas
A
Limmer
Tim
T
Sparwasser
Andreas
A
Hirner
Percy A
PA
Knolle
Jörg C
JC
Kalff
Christian
C
Kurts
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003713:Dendritic Cells / Q000378:metabolism*; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D006801:Humans; D045823:Ileus / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control*; D007156:Immunologic Memory / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011183:Postoperative Complications / Q000276:immunology*; D011409:Propylene Glycols / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D018709:Statistics, Nonparametric; D018417:Th1 Cells / Q000276:immunology
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D018664:Interleukin-12; D007371:Interferon-gamma; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine