Genetic deletion of JNK1 and JNK2 aggravates the DSS-induced colitis in mice.
The c-Jun N-terminal kinases (JNKs) are considered as novel targets for therapy of inflammatory bowel diseases (IBD). However, the relevant JNK isoforms have to be elucidated. Here, we analyze the individual contribution of the JNK1 and JNK2 isoforms in a dextran sulfate sodium (DSS) model of experimental colitis. JNK1 and JNK2 knockout mice (JNK1 ko, JNK2 ko) and their wild-type controls (WT1, WT2) received three cycles of DSS treatment, each consisting of 1.7% DSS for 5 days, followed by 5 days with water. Animals were daily evaluated by a disease activity index (DAI) comprising measurement of body weight, estimation of stool consistency, and test for occult blood/gross rectal bleeding. After 30 days all animals were sacrificed, and the inflamed intestine was histologically evaluated by a crypt damage score. Unexpectedly, neither JNK1 ko nor JNK2 ko prevented mice from developing a chronic colitis when compared to wild-type controls WT1 and WT2, respectively. On the contrary, DAI and mortality were aggravated in JNK2 ko compared to WT2. DAI and mortality did not differ between JNK1 ko and WT1, but the histological crypt damage score was significantly enhanced in the cecum of JNK1 ko mice. Genetic deletion of JNK2 worsens the disease outcome in an experimental model of murine colitis. We hypothesize that the functional deletion of the otherwise proapoptotic JNK2 prolongs the activity of proinflammatory immune cells with deterioration of disease activity.
Chromik
A M
AM
Department of General and Visceral Surgery, St. Josef Hospital, Ruhr-University of Bochum, Bochum, Germany. a.chromik@klinikum-bochum.de
Müller
A M
AM
Körner
J
J
Belyaev
O
O
Holland-Letz
T
T
Schmitz
F
F
Herdegen
T
T
Uhl
W
W
Mittelkötter
U
U
D000818:Animals; D017209:Apoptosis; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D003433:Crosses, Genetic; D016264:Dextran Sulfate / Q000633:toxicity; D006471:Gastrointestinal Hemorrhage / Q000209:etiology; D007413:Intestinal Mucosa / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016037:Single-Blind Method; D015431:Weight Loss
D016264:Dextran Sulfate; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8