Macrophage ablation attenuates adenoviral vector-induced pancreatitis.
BACKGROUND
The objective of these studies is to determine the effects of macrophage ablation on the course of acute viral pancreatitis. Macrophages secrete proinflammatory cytokines triggering local pancreatic and systemic inflammation in the acute phase of virus-induced pancreatitis. We hypothesized that ablation of macrophages should attenuate the host inflammatory response in a mouse model of adenovirus-induced pancreatitis.


METHODS
Liposome-encapsulated dichloromethylene-diphosphonate, a macrophage-depleting agent, was used before direct pancreatic injection of a recombinant adenovirus expressing a marker gene in C57Bl/6 and IL-6 knockout (KO) mice.


RESULTS
C57Bl/6 mice depleted of macrophages had diminished pancreatic inflammation in the first 24 hours after vector administration. IL-6 KO mice depleted of macrophages had more severe inflammation than similarly treated C57Bl/6 mice. C57Bl/6 mice depleted of macrophages, and IL-6 KO mice had prolonged transgene expression and diminished cytotoxic T lymphocyte responses to adenoviral vector. Mortality was highest in IL-6 KO mice depleted of macrophages. Depletion of macrophages also prevented detectable serum IL-6, IL-10, or IL-12 levels in C57Bl/6 mice.


CONCLUSIONS
The data suggest that macrophages play a role in the acute inflammatory response to viral vector-induced pancreatitis and that IL-6 may be protective. Understanding of the mechanisms that initiate the host immune cascade will allow more effective use of adenoviral vector-based pancreatic gene delivery.
Shifrin
Alexander L
AL
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, USA.
Chirmule
Narendra
N
Zhang
Yi
Y
Raper
Steven E
SE
D000208:Acute Disease; D000256:Adenoviridae; D000818:Animals; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors; D008264:Macrophages / Q000187:drug effects*; D008697:Methane / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010195:Pancreatitis / Q000188:drug therapy* / Q000473:pathology / Q000821:virology*
D004164:Diphosphonates; C118184:LE-Cl2MDP; D008697:Methane