title: Topical imiquimod treatment prevents UV-light induced loss of contact hypersensitivity and immune tolerance.
abstract: Imiquimod (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine) is a TLR7 agonist that induces cytokine production in TLR7 bearing antigen-presenting cells (APCs), including IL-12, a cytokine that has been demonstrated to be a critical effector molecule for contact hypersensitivity (CHS). To test our hypothesis that topical applications of imiquimod may protect the skin immune system against the deleterious effects of UV light exposures, we treated animals with this agent, or its vehicle or nothing before UV exposures. Although topical imiquimod exposures before UV light did not prevent the depletion of epidermal Langerhans cells, it did prevent the loss of CHS. IL-12 was important in the protective role of imiquimod in preventing UV-induced loss of CHS, as systemic treatment of mice with an anti-IL-12 p70 monoclonal antibody blocked the protective effects of imiquimod. Additionally, only imiquimod-treated mice were resistant to hapten-specific tolerance induction after UV irradiation at the site of the initial sensitization with the hapten 2,4 dinitro-1-fluorobenzene. To model for the effects of TLR7 activation on the UV effect on antigen-APCs, XS52 cell line was used to study this interaction in an in vitro model system. This cell line expressed mRNA for TLR7, downregulated IkappaB, phosphorylated c-Jun N-terminal kinase, and secreted cytokines after exposure to imiquimod or lipopolysaccharide. Activation of the TLR7 signaling pathway on XS52 before UV-light exposures enhanced IL-12p70 secretion by this cell line. Similarly, activation of TLR7 on XS52 before UV-light exposure also prevented the UV-induced loss of IFN-gamma triggering in T cells during an allogeneic mixed lymphocyte reaction. Imiquimod-treated, UV-irradiated XS52 triggered a more vigorous IFN-gamma production than did either imiquimod-treated XS52 or UV-irradiated XS52, again suggesting a synergy between the two treatments. Lastly, enriched lymph node CD11c+ APCs from mice treated with UV irradiation, imiquimod alone or the combination of UV irradiation and imiquimod indicated the same in vivo synergy between imiquimod irradiation and UV irradiation in enhancing IL-12p70 production. These data suggest that topical imiquimod applications may play a role in preventing UV-induced impairment of the skin immune system, which is thought to be one of the critical events that allow the development of UV-induced skin cancers.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Rochester School of Medicine, Rochester, New York, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Thatcher
authors.forename: Irina
authors.initials: I
authors.lastname: Luzina
authors.forename: Rita
authors.initials: R
authors.lastname: Fishelevich
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tomai
authors.forename: Richard L
authors.initials: RL
authors.lastname: Miller
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Gaspari
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000634:Aminoquinolines / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003877:Dermatitis, Contact / Q000517:prevention & control*; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D000077271:Imiquimod; D007108:Immune Tolerance / Q000187:drug effects*; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007801:Langerhans Cells / Q000187:drug effects* / Q000528:radiation effects; D008562:Membrane Glycoproteins / Q000819:agonists; D051379:Mice; D008810:Mice, Inbred C57BL; D012867:Skin / Q000187:drug effects* / Q000528:radiation effects; D051199:Toll-Like Receptor 7 / Q000819:agonists; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000911:Antibodies, Monoclonal; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D018664:Interleukin-12; D007371:Interferon-gamma; D000077271:Imiquimod