Intra-colonic administration of the TLR7 agonist R-848 induces an acute local and systemic inflammation in mice.
Imidazoquinoline compounds, such as resiquimod (R-848), are well known topically active immune modifiers that bind to toll-like receptor 7 (TLR7). The aim of this study was to characterize the R-848 induced inflammatory response in mice and to validate the response using methyl-prednisolone and anti-TNF antibody. Intra-colonic application of R-848 to BALB/c mice induced a systemic transient elevation of TNF, CXCL1, IL-6, and IL-12p40 and a colonic elevation of cytokines/chemokines and iNOS, without infiltration of immune cells or epithelial destruction. Treatment with methyl-prednisolone or anti-TNF antibody attenuated the systemic (TNF, IL-6, IL-12p40, and CXCL1) and local (colonic TNF and iNOS mRNA expression) response induced by R-848. In summary, intra-colonic administration of R-848 induces an acute systemic and local inflammatory response, which can be attenuated by steroids or anti-TNF antibody. We suggest that the R-848 inflammatory model can be useful in future validation of new drugs for gastrointestinal inflammatory conditions.
Karlsson
Agneta
A
Department of Integrative Pharmacology, AstraZeneca R&D Mölndal, Sweden.
Jägervall
Ke
K
Utkovic
Helena
H
Karlsson
Lisa
L
Rehnström
Erika
E
Fredin
Maria Fritsch
MF
Gillberg
Per-Göran
PG
Jansson
Liselotte
L
Michaëlsson
Erik
E
Melgar
Silvia
S
D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage*; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D007155:Immunologic Factors / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors*
D016207:Cytokines; D007093:Imidazoles; D007155:Immunologic Factors; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C402365:resiquimod