Whole-Body In Vivo Monitoring of Inflammatory Diseases Exploiting Human Interleukin 6-Luciferase Transgenic Mice.
Chronic inflammation underlies the pathological progression of various diseases, and thus many efforts have been made to quantitatively evaluate the inflammatory status of the diseases. In this study, we generated a highly sensitive inflammation-monitoring mouse system using a bacterial artificial chromosome (BAC) clone containing extended flanking sequences of the human interleukin 6 gene (hIL6) locus, in which the luciferase (Luc) reporter gene is integrated (hIL6-BAC-Luc). We successfully monitored lipopolysaccharide-induced systemic inflammation in various tissues of the hIL6-BAC-Luc mice using an in vivo bioluminescence imaging system. When two chronic inflammatory disease models, i.e., a genetic model of atopic dermatitis and a model of experimental autoimmune encephalomyelitis (EAE), were applied to the hIL6-BAC-Luc mice, luciferase bioluminescence was specifically detected in the atopic skin lesion and central nervous system, respectively. Moreover, the Luc activities correlated well with the disease severity. Nrf2 is a master transcription factor that regulates antioxidative and detoxification enzyme genes. Upon EAE induction, the Nrf2-deficient mice crossed with the hIL6-BAC-Luc mice exhibited enhanced neurological symptoms concomitantly with robust luciferase luminescence in the neuronal tissue. Thus, whole-body in vivo monitoring using the hIL6-BAC-Luc transgenic system (WIM-6 system) provides a new and powerful diagnostic tool for real-time in vivo monitoring of inflammatory status in multiple different disease models.
Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Makiko
M
Hayashi
Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Jun
J
Takai
Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Lei
L
Yu
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Hozumi
H
Motohashi
Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan moriguch@med.tohoku.ac.jp masiyamamoto@med.tohoku.ac.jp.
Takashi
T
Moriguchi
Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan moriguch@med.tohoku.ac.jp masiyamamoto@med.tohoku.ac.jp.
Masayuki
M
Yamamoto
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D018805:Sepsis / Q000276:immunology / Q000378:metabolism; D051598:Whole Body Imaging
D000893:Anti-Inflammatory Agents; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D003907:Dexamethasone; D049409:Luciferases, Firefly