CCL-34, a synthetic toll-like receptor 4 activator, modulates differentiation and maturation of myeloid dendritic cells
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Shu-Ling Fu1, Chun-Cheng Lin2, Ming-Ling Hsu3, Sheng-Hung Liu1, Yu-Chuen Huang4, Yu-Jen Chen1,3,5
1Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan
2Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan
3Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
4School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
5Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan
Yu-Jen Chen, e-mail: firstname.lastname@example.org
Keywords: CCL-34, TLR4, dendritic cell, differentiation, maturation
Received: June 21, 2015 Accepted: January 26, 2016 Published: February 11, 2016
CCL-34, a synthetic α-galactosylceramide analog, has been reported as an activator of toll-like receptor 4 (TLR4) in macrophages. TLR4 is highly expressed in dendritic cell (DC) and several TLR4 agonists are known to trigger DC maturation. We herein evaluated the effect of CCL-34 on DC maturation. Human CD14+ monocyte-derived immature DC were treated with CCL-34, its inactive structural analog CCL-44, or LPS to assess the DC maturation. CCL-34 induced DC maturation according to their characteristically dendrite-forming morphology, CD83 expression and IL-12p70 production. The allostimulatory activity of DC on proliferation of naive CD4+CD45+RA+ T cells and their secretion of interferon-γ was increased by CCL-34. Phagocytosis, an important function of immature DC, was reduced after CCL-34 treatment. All these effects related to DC maturation were evidently induced by positive control LPS but not by CCL-44 treatment. TLR4 neutralization impaired human DC maturation triggered by CCL-34. The induction of IL-12, a hallmark of DC maturation, by CCL-34 and LPS was only evident in TLR4-competent C3H/HeN, but not in TLR4-defective C3H/HeJ mice. CCL-34 could further elicit the antigen presentation capability in mice inoculated with doxorubicin-treated colorectal cancer cells. In summary, CCL-34 triggers DC maturation via a TLR4-dependent manner, which supports its potential application as an immunostimulator.
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