Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice.
OBJECTIVE
Trinitrobenzene sulfonic acid (TNBS)-induced colitis is a T-helper 1 (Th1) T cell-mediated inflammation that is rapidly reversed by administration of anti-interleukin (IL) 12. This study sought to define the mechanism of this curative effect.


METHODS
Cells and tissue from mice with TNBS colitis receiving treatment with anticytokines were analyzed for phenotype, cytokine production, and apoptosis.


RESULTS
In initial studies, we found that treatment of mice with TNBS-induced colitis with anti-IL-12 was more effective than with anti-interferon (IFN)-gamma, and that anti-IL-12 led to complete normalization of IFN-gamma production by lamina propria T cells ex vivo, whereas anti-IFN-gamma did not. These data suggesting that anti-IL-12 leads to reversal of colitis by elimination of the Th1 T cells were substantiated by studies showing that anti-IL-12 treatment led to increased numbers of apoptotic cells in the lamina propria and spleen by both TUNEL staining of tissues and dispersed spleen cell populations. Finally, we found that the observed apoptosis was mediated by the Fas pathway because (1) MRL/MpJ-lpr(fas) mice lacking Fas function develop colitis that responds poorly to treatment with anti-IL-12; and (2) SJL/J mice with TNBS colitis that received Fas-Fc to block the Fas pathway were resistant to anti-IL-12 treatment.


CONCLUSIONS
These studies show that a main mechanism of action of anti-IL-12 in TNBS-induced colitis is the induction of Fas-mediated apoptosis of the Th1 T cells, causing inflammation.
Fuss
I J
IJ
Mucosal Immunity Section, National Institutes of Health, Bethesda, Maryland, USA.
Marth
T
T
Neurath
M F
MF
Pearlstein
G R
GR
Jain
A
A
Strober
W
W
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D018417:Th1 Cells / Q000187:drug effects* / Q000502:physiology; D014302:Trinitrobenzenesulfonic Acid; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology
D000906:Antibodies; D019014:fas Receptor; D018664:Interleukin-12; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid