Quinacrine inhibits the epidermal dendritic cell migration initiating T cell-mediated skin inflammation

Abstract

Quinacrine (QC) is an anti-inflammatory drug that has been used for the treatment of malaria and rheumatoid diseases. The mechanism(s) underlying the anti-inflammatory activity of QC remains poorly understood. We recently reported the QC-mediated inhibition of the NF-kappaB pathway using an in vitro model. To test this potential mechanism in vivo, we used the contact hypersensitivity response (CHS) to chemical allergen sensitization and challenge in mice as a model of skin inflammation. The results indicated that QC treatment inhibited NF-kappaB activation in the skin during allergen sensitization. This inhibition was reflected by decreased mRNA expression and protein production of the NF-kappaB-dependent cytokines TNF-alpha and IL-1beta and the chemokine CCL21 in the skin. The decreases in these cytokines resulted in reduced migration of allergen-presenting dendritic cells from the skin into skin-draining lymph nodes and markedly decreased activation of effector CD8+ T cells for the CHS response to allergen challenge (inhibitory concentration 50% or IC50 was 55 mg/kg). These findings reveal a previously unrecognized mechanism of QC-mediated inhibition of inflammation.