The small antitumoral immune response modifier imiquimod interacts
with adenosine receptor signaling in a TLR7- and TLR8-independent
fashion
M. Schon, M. Schon, and K. Klotz. J Invest Dermatol, 126 (6):
1338-47(June 2006)Schon, Michael P Schon, Margarete Klotz, Karl-Norbert Research Support,
Non-U.S. Gov't United States The Journal of investigative dermatology
J Invest Dermatol. 2006 Jun;126(6):1338-47..
Abstract
Imiquimod, a small-molecule immune response modifier of the imidazoquinoline
family, has shown profound antitumoral and antiviral efficacy both
in vitro and in clinical applications in vivo. It has been demonstrated
that this activity is mediated through the Toll-like receptor (TLR)7-
and TLR8-signaling cascade resulting in the secretion of proinflammatory
cytokines and, consecutively, induction of a tumor-directed cellular
immune response. In addition, imiquimod exerts a direct proapoptotic
activity in tumor cells. We demonstrate here that imiquimod induces
activation of the transcription factor NF-kappaB and the downstream
production of proinflammatory cytokines in the absence of TLR7 and
TLR8. In Chinese hamster ovary cells stably transfected with the
human adenosine receptor subtypes, we then show in radioligand-binding
competition experiments that imiquimod binds to adenosine receptors
at concentrations relevant in clinical settings, with highest affinities
to the A(1) and A(2A) subtypes. The effect on the receptor-mediated
activation of adenylyl cyclase was also studied, and these experiments
revealed that imiquimod acts as an adenosine receptor antagonist.
In addition, imiquimod had an inhibitory effect on adenylyl cyclase
activity downstream from the receptor. Finally, using transformed
human keratinocytes, we provide experimental evidence that imiquimod
and A(2A) adenosine receptor-specific compounds similarly induce
proinflammatory cytokines in the absence of immune cells. Thus, imiquimod
appears to suppress an important feedback mechanism of inflammation
by antagonism of adenosine receptor-dependent increase of cAMP and
a concomitant receptor-independent inhibition of cAMP production.
These novel mechanisms presumably act synergistic with the positive
induction of proinflammatory cytokines and can, at least in part,
explain the profound inflammation observed in some patients in vivo.
Schon, Michael P Schon, Margarete Klotz, Karl-Norbert Research Support,
Non-U.S. Gov't United States The Journal of investigative dermatology
J Invest Dermatol. 2006 Jun;126(6):1338-47.
%0 Journal Article
%1 Schon2006
%A Schon, M. P.
%A Schon, M.
%A Klotz, K. N.
%D 2006
%J J Invest Dermatol
%K & 7/genetics/*physiology 8/genetics/*physiology Adjuvants, Agents/*pharmacology Aminoquinolines/*pharmacology Animals Antineoplastic B/agonists CHO Cell Cricetinae Cricetulus Cytokines/genetics/metabolism Humans Immunologic/*pharmacology Line, Mutation NF-kappa P1/agonists/antagonists Purinergic Receptor Toll-Like Tumor effects inhibitors/*drug
%N 6
%P 1338-47
%T The small antitumoral immune response modifier imiquimod interacts
with adenosine receptor signaling in a TLR7- and TLR8-independent
fashion
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16575388
%V 126
%X Imiquimod, a small-molecule immune response modifier of the imidazoquinoline
family, has shown profound antitumoral and antiviral efficacy both
in vitro and in clinical applications in vivo. It has been demonstrated
that this activity is mediated through the Toll-like receptor (TLR)7-
and TLR8-signaling cascade resulting in the secretion of proinflammatory
cytokines and, consecutively, induction of a tumor-directed cellular
immune response. In addition, imiquimod exerts a direct proapoptotic
activity in tumor cells. We demonstrate here that imiquimod induces
activation of the transcription factor NF-kappaB and the downstream
production of proinflammatory cytokines in the absence of TLR7 and
TLR8. In Chinese hamster ovary cells stably transfected with the
human adenosine receptor subtypes, we then show in radioligand-binding
competition experiments that imiquimod binds to adenosine receptors
at concentrations relevant in clinical settings, with highest affinities
to the A(1) and A(2A) subtypes. The effect on the receptor-mediated
activation of adenylyl cyclase was also studied, and these experiments
revealed that imiquimod acts as an adenosine receptor antagonist.
In addition, imiquimod had an inhibitory effect on adenylyl cyclase
activity downstream from the receptor. Finally, using transformed
human keratinocytes, we provide experimental evidence that imiquimod
and A(2A) adenosine receptor-specific compounds similarly induce
proinflammatory cytokines in the absence of immune cells. Thus, imiquimod
appears to suppress an important feedback mechanism of inflammation
by antagonism of adenosine receptor-dependent increase of cAMP and
a concomitant receptor-independent inhibition of cAMP production.
These novel mechanisms presumably act synergistic with the positive
induction of proinflammatory cytokines and can, at least in part,
explain the profound inflammation observed in some patients in vivo.
@article{Schon2006,
abstract = {Imiquimod, a small-molecule immune response modifier of the imidazoquinoline
family, has shown profound antitumoral and antiviral efficacy both
in vitro and in clinical applications in vivo. It has been demonstrated
that this activity is mediated through the Toll-like receptor (TLR)7-
and TLR8-signaling cascade resulting in the secretion of proinflammatory
cytokines and, consecutively, induction of a tumor-directed cellular
immune response. In addition, imiquimod exerts a direct proapoptotic
activity in tumor cells. We demonstrate here that imiquimod induces
activation of the transcription factor NF-kappaB and the downstream
production of proinflammatory cytokines in the absence of TLR7 and
TLR8. In Chinese hamster ovary cells stably transfected with the
human adenosine receptor subtypes, we then show in radioligand-binding
competition experiments that imiquimod binds to adenosine receptors
at concentrations relevant in clinical settings, with highest affinities
to the A(1) and A(2A) subtypes. The effect on the receptor-mediated
activation of adenylyl cyclase was also studied, and these experiments
revealed that imiquimod acts as an adenosine receptor antagonist.
In addition, imiquimod had an inhibitory effect on adenylyl cyclase
activity downstream from the receptor. Finally, using transformed
human keratinocytes, we provide experimental evidence that imiquimod
and A(2A) adenosine receptor-specific compounds similarly induce
proinflammatory cytokines in the absence of immune cells. Thus, imiquimod
appears to suppress an important feedback mechanism of inflammation
by antagonism of adenosine receptor-dependent increase of cAMP and
a concomitant receptor-independent inhibition of cAMP production.
These novel mechanisms presumably act synergistic with the positive
induction of proinflammatory cytokines and can, at least in part,
explain the profound inflammation observed in some patients in vivo.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Schon, M. P. and Schon, M. and Klotz, K. N.},
biburl = {https://www.bibsonomy.org/bibtex/2659cd770084ec2ee7844a7c173ec9881/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {71b730990e1472cc913a45ba4a1dd4e9},
intrahash = {659cd770084ec2ee7844a7c173ec9881},
issn = {0022-202X (Print) 0022-202X (Linking)},
journal = {J Invest Dermatol},
keywords = {& 7/genetics/*physiology 8/genetics/*physiology Adjuvants, Agents/*pharmacology Aminoquinolines/*pharmacology Animals Antineoplastic B/agonists CHO Cell Cricetinae Cricetulus Cytokines/genetics/metabolism Humans Immunologic/*pharmacology Line, Mutation NF-kappa P1/agonists/antagonists Purinergic Receptor Toll-Like Tumor effects inhibitors/*drug},
month = Jun,
note = {Schon, Michael P Schon, Margarete Klotz, Karl-Norbert Research Support,
Non-U.S. Gov't United States The Journal of investigative dermatology
J Invest Dermatol. 2006 Jun;126(6):1338-47.},
number = 6,
pages = {1338-47},
shorttitle = {The small antitumoral immune response modifier imiquimod interacts
with adenosine receptor signaling in a TLR7- and TLR8-independent
fashion},
timestamp = {2010-12-14T18:20:41.000+0100},
title = {The small antitumoral immune response modifier imiquimod interacts
with adenosine receptor signaling in a TLR7- and TLR8-independent
fashion},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16575388},
volume = 126,
year = 2006
}