Double-stranded RNA induces melanocyte death via activation of Toll-like receptor 3.
As cutaneous pigment-producing cells, melanocytes can become targets of primary and secondary immune response as can be seen in diseases like vitiligo and Vogt-Koyanagi-Harada (VKH) syndrome. Viral infections have previously been implicated as a possible precipitating factor in the destruction of melanocytes in these disorders. During viral replication, double-stranded RNA (dsRNA) is produced as an intermediate metabolite, which induces antiviral and inflammatory responses through Toll-like receptor 3 (TLR3) in cells of innate immune system. The functional responses of melanocytes to dsRNA, however, remain unclear. Herein, we demonstrated that human melanocytes expressed TLR3 at a constitutive and inducible level. Stimulation with poly(I:C), a synthetic dsRNA analogue, triggered apoptosis of melanocytes. The apoptosis-inducing effect was shown by RNA interference to be largely dependent on TLR3, but occurred independently of NF-κB activation since treatment with specific NF-κB inhibitor Bay 11-7082 failed to prevent the process. In contrast, IFN-β neutralizing Ab blocked the apoptosis-inducing effect of dsRNA, indicating the involvement of IFN-β autocrine signalling. Furthermore, studies on the intracellular signal transduction pathways revealed that dsRNA induces the activation of p38, ERK1/2 and JNK1/2 in melanocytes. Using specific inhibitors, we demonstrated that activation of p38 and ERK1/2 controlled both IFN-β secretion and IFN-β mediated cell death. Taken together, these data suggest that viral dsRNA stimulates TLR3 in human melanocytes and triggers the cellular apoptosis through autocrine of IFN-β.
Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
Ning
N
Yu
Shujie
S
Zhang
Tao
T
Sun
Kefei
K
Kang
Ming
M
Guan
Leihong
L
Xiang
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D016899:Interferon-beta / Q000378:metabolism*; D008297:Male; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007369:Interferon Inducers; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D048056:Mitogen-Activated Protein Kinase 9; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D011070:Poly I-C