IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner.
BACKGROUND
In murine models of inflammatory bowel disease, colonic inflammation is considered to be caused by an aberrant Th1-type immune response.


OBJECTIVE
To investigate if systemic administration of interleukin (IL)-12 and IL-18 to wild-type BALB/c mice induces liver injury and intestinal inflammation, and if pathological changes are observed, what cytokines are involved.


METHODS
Mice (BALB/c-wild-type (wt), MRL-lpr/lpr, BALB/c-interferon gamma knock out (IFN-gamma KO), C57BL/6-inducible nitric oxide synthase (iNOS) KO, and BALB/c tumour necrosis factor alpha (TNF-alpha) KO) were injected intraperitoneally each day with IL-12 (20 ng/g/mouse) and/or IL-18 (200 ng/g/mouse).


RESULTS
Administration of IL-12 and IL-18 to BALB/c-wt mice induced prominent intestinal mucosal inflammation and fatty liver, leading to piloerection, bloody diarrhoea, and weight loss. IL-12 and IL-18 induced striking elevations in serum levels of IFN-gamma that caused NO production, although increased NO had no exacerbating effect on mice. Moreover, iNOS KO mice, or MRL lpr/lpr mice lacking functional Fas were equally susceptible to IL-12 and IL-18. Administration of IL-12 and IL-18 did not induce TNF-alpha production in wild-type mice, and the same treatment to TNF-alpha KO mice induced intestinal mucosal inflammation. Furthermore, they had diffuse and dense infiltration of small fat droplets in their hepatocytes associated with an increase in serum levels of liver enzymes. In contrast, the same treatment in IFN-gamma KO BALB/c mice and iNOS KO mice did not induce these changes.


CONCLUSIONS
Our study strongly indicates that IL-18 together with IL-12 induces intestinal mucosal inflammation in an IFN-gamma dependent but TNF-alpha, NO, and Fas ligand independent manner, and fatty liver is dependent on IFN-gamma and NO.
Chikano
S
S
Fourth Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501 Japan. chikano-gi@umin.ac.jp
Sawada
K
K
Shimoyama
T
T
Kashiwamura
S I
SI
Sugihara
A
A
Sekikawa
K
K
Terada
N
N
Nakanishi
K
K
Okamura
H
H
D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced* / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000009:adverse effects*; D020382:Interleukin-18 / Q000009:adverse effects*; D007413:Intestinal Mucosa / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II
D020382:Interleukin-18; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse