Abstract
Imiquimod is known to exert its effects through Toll-like receptor 7 (TLR7) and/or TLR8, resulting in expression of proinflammatory cytokines and chemokines. Keratinocytes have not been reported to constitutively express TLR7 and TLR8, and the action of imiquimod is thought to be mediated by the adenine receptor, not TLR7 or TLR8. In this study, we revealed the expression of TLR7 in keratinocytes after calcium-induced differentiation. After addition of calcium to cultured keratinocytes, the immunological responses induced by imiquimod, such as activation of NF-κB and induction of TNF-α and IL-8, were more rapid and stronger. In addition, imiquimod induced the expression TLR7, and acted synergistically with calcium to induce proinflammatory cytokines. We confirmed that the responses induced by imiquimod were significantly inhibited by microRNAs suppressing TLR7 expression. These results suggest that TLR7 expressed in keratinocytes play key roles in the activation of NF-κB signaling by imiquimod, and that their modulation in keratinocytes could provide therapeutic potential for many inflammatory skin diseases.
Highlights
Recent studies have shown that engagement of Toll-likereceptors (TLRs), types of pattern recognition receptors that recognize pathogen-associated molecular patterns present in microbes, play significant roles in both innate and adaptive immunity [1,2,3]
We found that imiquimod induced the expression of Toll-like receptor 7 (TLR7) in both non-differentiated keratinocytes and differentiated keratinocytes by calcium treatment for 7 days (Figure 2A, Figure S1)
Imiquimod has been demonstrated to exert its biological activity through direct activation of TLR7 and/or TLR8, both of which were recently identified as natural receptors for single-stranded RNA [11,20,21]
Summary
Recent studies have shown that engagement of Toll-likereceptors (TLRs), types of pattern recognition receptors that recognize pathogen-associated molecular patterns present in microbes, play significant roles in both innate and adaptive immunity [1,2,3]. The responsiveness of nucleic acid-sensing TLRs has a profound impact on immune responses, leading to the production of pro-inflammatory cytokines and up-regulation of co-stimulatory molecules necessary for the adaptive immune response [6,7,8]. Cells of the innate immune defense system recognize the pathogen-associated molecular structures via various TLRs [9,10]. Keratinocytes express various TLRs, and participate in innate immune response actively. Stimulation of keratinocytes with TLR ligands results in different immunological responses, leading to nuclear translocation of nuclear factor (NF)-kB and resulting in the production of interleukin (IL)-8, macrophage inflammatory protein-3a (CCL20), and cutaneous T-cell-attracting chemokine (CCL27) [11,12]
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