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 thehIL6 -BAC-Luc mice using anin 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 thehIL6 -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 thehIL6 -BAC-Luc mice exhibited enhanced neurological symptoms concomitantly with robust luciferase luminescence in the neuronal tissue. Thus, whole-bodyin vivo monitoring using thehIL6 -BAC-Luc transgenic system (WIM-6 system) provides a new and powerful diagnostic tool for real-timein vivo monitoring of inflammatory status in multiple different disease models.