期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 51, 期 4, 页码 965-977出版社
WILEY
DOI: 10.1002/eji.202048813
关键词
alpha‐ lactalbumin; dendritic cells; HAMLET; macrophages; myeloid cells
类别
资金
- Swedish Medical Research Council (VR) [K2015-99X-22878, 2018/05947, 2018/05795]
- Royal Physiographic Society in Lund
- Swedish Society for Medical Research (SSMF)
- Swedish Research Council [2018-05947, 2018-05795] Funding Source: Swedish Research Council
HAMLET is a protein-lipid complex with specific antibacterial and antitumor activity, lacking cytotoxicity against healthy cells, while stimulating immune cells in humans and mice, inducing a pro-inflammatory response and enhancing the clearance of bacteria by activated immune cells.
HAMLET is a protein-lipid complex with a specific and broad bactericidal and tumoricidal activity, that lacks cytotoxic activity against healthy cells. In this study, we show that HAMLET also has general immune-stimulatory effects on primary human monocyte-derived dendritic cells and macrophages (Mo-DC and Mo-M) and murine RAW264.7 macrophages. HAMLET, but not its components alpha-lactalbumin or oleic acid, induces mature CD14(low/-)CD83(+) Mo-DC and M1-like CD14(+)CD86(++) Mo-M surface phenotypes. Concomitantly, inflammatory mediators, including IL-2, IL-6, IL-10, IL-12 and MIP-1 alpha, were released in the supernatant of HAMLET-stimulated cells, indicating a mainly pro-inflammatory phenotype. The HAMLET-induced phenotype was mediated by calcium, NF kappa B and p38 MAPK signaling in Mo-DCs and calcium, NF kappa B and ERK signaling in Mo-M as inhibitors of these pathways almost completely blocked the induction of mature Mo-DCs and M1-like Mo-M. Compared to unstimulated Mo-DCs, HAMLET-stimulated Mo-DCs were more potent in inducing T cell proliferation and HAMLET-stimulated macrophages were more efficient in phagocytosis of Streptococcus pneumoniae in vitro. This indicates a functionally activated phenotype of HAMLET-stimulated DCs and macrophages. Combined, we propose that HAMLET has a two-fold anti-bacterial activity; one inducing direct cytotoxic activity, the other indirectly mediating elimination of bacteria by activation of immune cells of the myeloid lineage.
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