Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream.
BACKGROUND
The objective of this study was to identify the molecular processes responsible for the anti-lesional activity of imiquimod in subjects with actinic keratosis using global gene expression profiling.


METHODS
A double-blind, placebo-controlled, randomized study was conducted to evaluate gene expression changes in actinic keratosis treated with imiquimod 5% cream. Male subjects (N = 17) with > or = 5 actinic keratosis on the scalp applied placebo cream or imiquimod 3 times a week on nonconsecutive days for 4 weeks. To elucidate the molecular processes involved in actinic keratosis lesion regression by imiquimod, gene expression analysis using oligonucleotide arrays and real time reverse transcriptase polymerase chain reaction were performed on shave biopsies of lesions taken before and after treatment.


RESULTS
Imiquimod modulated the expression of a large number of genes important in both the innate and adaptive immune response, including increased expression of interferon-inducible genes with known antiviral, anti-proliferative and immune modulatory activity, as well as various Toll-like receptors. In addition, imiquimod increased the expression of genes associated with activation of macrophages, dendritic cells, cytotoxic T cells, and natural killer cells, as well as activation of apoptotic pathways.


CONCLUSIONS
Data suggest that topical application of imiquimod stimulates cells in the skin to secrete cytokines and chemokines that lead to inflammatory cell influx into the lesions and subsequent apoptotic and immune cell-mediated destruction of lesions.
Torres
Abel
A
Dermatology Office, Loma Linda University Medical Center, Loma Linda, California, USA. abelt@aol.com
Storey
Leslie
L
Anders
Makala
M
Miller
Richard L
RL
Bulbulian
Barbara J
BJ
Jin
Jizhong
J
Raghavan
Shalini
S
Lee
James
J
Slade
Herbert B
HB
Birmachu
Woubalem
W
D056704:Adaptive Immunity / Q000187:drug effects / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000287:Administration, Topical; D000368:Aged; D000369:Aged, 80 and over; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003710:Demography; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004304:Dosage Forms; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000077271:Imiquimod; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D007370:Interferon Type I / Q000494:pharmacology; D055623:Keratosis, Actinic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015203:Reproducibility of Results; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D018925:Chemokines; D004304:Dosage Forms; D007370:Interferon Type I; D051192:Receptors, Pattern Recognition; D000077271:Imiquimod