Transcription factor NFATc2 controls the emergence of colon cancer associated with IL-6-dependent colitis.
NFAT transcription factors control T-cell activation and function. Specifically, the transcription factor NFATc2 affects the regulation of cell differentiation and growth and plays a critical role in the development of colonic inflammation. Here, we used an experimental model of colitis-associated colorectal carcinoma to investigate the contribution of NFATc2 to the promotion of colonic tumors. Compared with wild-type animals that readily presented with multiple colon tumors, NFATc2-deficient mice were protected from tumor development. This observed decrease in colonic tumor progression was associated with reduced endoscopic inflammation, increased apoptosis of lamina propria T lymphocytes, and significantly reduced levels of the critical proinflammatory cytokines interleukin (IL)-21 and IL-6. Administration of hyper IL-6 abrogated protection from tumor progression in NFATc2-knockout mice and restored tumor incidence to control levels. Taken together, our findings highlight a pivotal role for NFATc2 in the establishment of inflammation-associated colorectal tumors mediated by control of IL-6 expression.
I. Medical Clinic, University of Erlangen-Nuremberg, Erlangen; Institute of Diabetes Research, Helmholtz Zentrum Muenchen, Neuherberg, Switzerland.
Katharina
K
Gerlach
Carolin
C
Daniel
Hans A
HA
Lehr
Alexei
A
Nikolaev
Thomas
T
Gerlach
Raja
R
Atreya
Stefan
S
Rose-John
Markus F
MF
Neurath
Benno
B
Weigmann
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000150:complications / Q000235:genetics* / Q000276:immunology; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000276:immunology
D015850:Interleukin-6; D050778:NFATC Transcription Factors