期刊
FASEB JOURNAL
卷 28, 期 9, 页码 3952-3964出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-251967
关键词
ShK; probiotic worm therapy; T lymphocytes; ion channel modulator; hookworm
资金
- U.S. National Institutes of Health (NIH) [R01 NS48252, NS073712, GM076063]
- Howard Hughes Medical Institutes Med into Grad Initiative
- NIH T32 award [GM088129]
- Human Hookworm Initiative of the Gates Foundation
- National Institute of Allergy and Infectious Diseases (NIAID) at NIH
- University of California, Irvine
- National Health and Medical Research Council of Australia
The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)-related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar-micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7-effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersensitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFN gamma production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases.
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