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Frontline Science: IL‐18 primes murine NK cells for proliferation by promoting protein synthesis, survival, and autophagy
Author(s) -
ElDarawish Yosif,
Li Wen,
Yamanishi Kyosuke,
Pencheva Magdalena,
Oka Naoto,
Yamanishi Hiromichi,
Matsuyama Tomohiro,
Tanaka Yoshimasa,
Minato Nagahiro,
Okamura Haruki
Publication year - 2018
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.1hi1017-396rr
Subject(s) - biology , microbiology and biotechnology , stat5 , interleukin 15 , pi3k/akt/mtor pathway , stat3 , priming (agriculture) , cell growth , interleukin 12 , il 2 receptor , atg5 , autophagy , t cell , signal transduction , cytokine , interleukin , immunology , cytotoxic t cell , apoptosis , immune system , in vitro , biochemistry , botany , germination , genetics
Combined stimulation by IL‐2 and IL‐18 effectively promotes proliferation of NK cells, whereas singular stimulation does not. In this study, synergistic effects of these cytokines on NK cells proliferation was analyzed, focusing on the roles of IL‐18. In splenic resting NK cells from IL‐18KO mice, IL‐18 rapidly activated NF‐κB independently of IL‐2, and activated or up‐regulated various molecules downstream of PI3K/AKT and mTOR, including S6, Bcl‐XL, ATG5, and LC3II, accompanying increases in cell growth and survival. Thus, IL‐18 alone was revealed to augment various cellular processes (gene transcription, protein synthesis, survival) in the absence or presence of IL‐2. Notably, combined IL‐18 and IL‐2 promoted autophagosome formation. In addition, priming NK cells with IL‐18 augmented IL‐2R, especially CD25, and enabled cells to respond to IL‐2, resulting in activation of STAT3 and STAT5, followed by increase of cyclin B1 leading to proliferation. However, IL‐2 alone failed to activate STAT3 or STAT5 in resting IL18KO NK cells. These results clarify the distinct roles of IL‐2 and IL‐18 in NK cell proliferation, and the intrinsic roles of IL‐18 in various cellular processes, suggesting a range of functions of IL‐18 expressed in an array of nonhematopoietic cells.