Molecular imaging of NF-kappaB in prostate tissue after systemic administration of IL-1 beta.
BACKGROUND
Activation of nuclear-factor kappaB (NF-kappaB) influences the transcription of number of genes, many of which participate in inflammatory responses and tumor development. A wide range of human cancers and inflammatory disorders express inappropriate regulation of NF-kappaB. The role of NF-kappaB in intraprostatic inflammation has not been elucidated.


METHODS
Using transgenic NF-kappaB-Luciferase Tag mice coupled to the luciferase reporter gene, we performed serial, noninvasive in vivo and ex vivo molecular imaging of NF-kappaB activation in the mouse body after systemic administration of mouse pro-inflammatory cytokines: TNF-alpha, IL-6, and IL-1 beta at 10 microg/kg body weights. In some experiments, pretreatment with dexamethasone (10 mg/kg) was used to modulate the cytokine-induced NF-kappaB-dependent luminescence in vivo.


RESULTS
Treatment of NF-kappaB-Luc mice with cytokines increased luminescence in a time- and organ- specific manner. Highest levels of NF-kappaB-dependent luminescence were observed approximately 3-4 hr after IL-1 beta administration. An important finding was the cumulative effect of IL-1 beta to activate NF-kappaB in the prostate during chronic administration.


CONCLUSIONS
The molecular imaging of NF-kappaB activity might be an attractive approach to distinguish the role of cytokine-induced NF-kappaB signaling in intraprostatic inflammation and prostate cancer development. Since dexamethasone, a known NF-kappaB inhibitor, could reduce the IL-1 beta-induced NF-kappaB-dependent luminescence in the prostate, NF-kappaB-Luc mice might be useful tool to screen potential candidate drugs for treatment of inflammation and tumor associated with aberrant NF-kappaB activity.
Vykhovanets
Eugene V
EV
Department of Urology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
Shukla
Sanjeev
S
MacLennan
Gregory T
GT
Resnick
Martin I
MI
Carlsen
Harald
H
Blomhoff
Rune
R
Gupta
Sanjay
S
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics*; D011467:Prostate / Q000187:drug effects / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D005938:Glucocorticoids; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D008156:Luciferases