Imiquimod has the potential to induce apoptosis in skin cancer cells, possibly by circumventing mechanisms developed by malignant tumors to resist apoptotic signals.
Toll-like receptor (TLR) ligands lead to the induction of proinflammatory cytokines and are potent enhancers of specific immune responses. We show here that a single systemic dose of R-848, a ligand for TLR7, potently enhanced hapten sensitization during the induction of contact hypersensitivity (CHS). However, R-848 administration also resulted in a rapid and almost complete depletion of leukocytes from the blood. This effect was transient and was associated with general induction of endothelial adhesiveness. In response to R-848, endothelial cells up-regulated adhesion molecules in vitro and in vivo and leukocytes exhibited increased rolling on endothelia in R-848-treated animals. Adhesion molecule induction appeared to be a direct effect, because endothelial cells expressed TLR7 in vitro and in vivo. After R-848 treatment, the tissue residence time of leukocytes was markedly prolonged in all major peripheral organs. The resulting transiently reduced availability of peripheral-blood leukocytes (PBLs) (
IntroductionToll-like receptors (TLRs) are a family of mammalian proteins expressed on a variety of cell types of the immune system. 1 TLRs are able to recognize specific patterns conserved in microorganisms. TLR triggering leads to the induction of inflammatory responses and induces the development of specific immunity. 1 Consequently, specific TLR ligands, such as polyinosinicpolycytidylic acid (poly I:C), lipopolysaccharide (LPS), imidazoquinolines, or CpG oligodeoxynucleotides, have been employed as powerful immune adjuvants and may enhance specific antitumor and antiviral immunity. 2,3 TLR7 is predominantly expressed by plasmacytoid dendritic cells (DCs), myeloid DCs, 4 and B cells 5 and recognizes ssRNA. 6,7 R-848 and the structurally related compound imiquimod (the active substance of the drug Aldara; 3M Pharmaceuticals, St Paul, MN) are artificial ligands for TLR7. 8,9 These imidazoquinolines are immune response modifiers that possess potent antiviral 10 and antitumoral activity when applied topically to the skin. 11 This activity is in part mediated by the induction of type I interferons and inflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) and interleukin-1␣ (IL-1␣). 12 Plasmacytoid DCs have been found to be major targets of R-848, producing large amounts of interferon-␣ and IL-12p40 as well as up-regulating activation markers in response to R-848 both in vitro 13,14 and in vivo. 14 In addition, topical imiquimod has been shown to induce emigration of resident LCs from murine skin, thereby amplifying allergic contact hypersensitivity (CHS) reactions 15 as well as inducing the migration of immature human DCs into draining lymph nodes of cancer patients. 16 Imidazoquinolines also strongly enhance T helper-1 (Th1)-type immune responses: They induce IL-12 in human Langerhans cells (LCs) 17 and lead to production of high amounts of IFN-␥ and to suppression of IL-4 and IL-5 production by T cells in cultures of human peripheral-blood leukocytes (PBLs) and murine spleen cells. 18 Interestingly, pe...
Background Imiquimod, a potent immunomodulator, not having a direct antiproliferative activity, was found to be effective in genital and cutaneous premalignancies and malignancies.As tumor development depends on blood vessel supply, the inhibition of angiogenesis could be responsible for the antitumor activity.Objective To find in a murine model whether imiquimod has antiangiogenic activity and whether this activity is mediated by locally induced cytokines.
MethodsThe study was performed in two cell lines: Skv human keratinocytes containing multiple integrated copies of HPV16 derived from bowenoid papulosis, and murine L1 lung sarcoma cells of Balb/c mice. The murine model of cutaneous angiogenesis was used to assess and count the new blood vessel formation. The mice were immunosuppressed by a total body X-ray irradiation and treated with 5% or 2.5% imiquimod cream before or after induction of angiogenesis with intradermally injected tumor cell suspension. In some experiments the mice were, in addition, treated intraperitoneally with monoclonal antibodies against murine IFN α , TNF γ or IL-18.Results Topical application of imiquimod on the murine skin resulted in reduction of angiogenesis ( P < 0.001) induced by intradermal injection of both human and mouse tumor cells, more pronounced when 5% cream was applied on three consecutive days. Antibodies against murine IFN γ , TNF α and IL-18 completely abolished the inhibitory effect of imiquimod on angiogenesis induced by murine L1 sacroma cells. When human Skv cells were used in angiogenesis assay, the effect of imiquimod was abolished by antibodies against IL-18 but not against TNF α , which may be due to overproduction of TNF α by Skv cells.Conclusions Antiangiogenic effect of imiquimod was found to be mediated by IL-18, probably through promoting production of INF γ , the most important inhibitor of angiogenesis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.