Frontline Science: IL-18 primes murine NK cells for proliferation by promoting protein synthesis, survival, and autophagy

Abstract

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.

Quantifying NK cell growth and survival changes in response to cytokines and regulatory checkpoint blockade helps identify optimal culture and expansion conditions

“…IL‐18 has been previously documented as a synergistic cytokine, enhancing function of NK cell stimulatory cytokines such as IL‐2, IL‐12, IL‐15, IL‐18, and IL‐21 through activation and metabolism pathways . Indeed, our results confirmed that combining IL‐15 and IL‐18 induced extremely rapid NK cell proliferation, far exceeding the rate of IL‐15 alone.…”

Low CD4⁺/CD25⁺/CD127⁻ regulatory T cell- and high INF-γ levels are associated with improved survival of neuroblastoma patients treated with long-term infusion of ch14.18/CHO combined with interleukin-2

“…Importantly, both cytokines were induced as a result of ch14.18/CHO and not IL- cytotoxic NK cells and cytotoxic T lymphocytes that may largely contribute to the clinical benefit. 39,[48][49][50] Since co-treatment with IL-2 led to a strong induction of immune suppressive T regs , the concomitant depletion of T regs during an IL-2 treatment or replacing IL-2 by cytokines which do not stimulate immune suppressive cell populations may represent potential strategies for future. [51][52][53] In summary, our study provides a mechanistic explanation for the absence of a beneficial role of IL-2 for immunotherapy with ch14.18/CHO as previously reported 13 due to its undesired expansion of immune regulatory T regs .…”

Current perspectives on the interleukin‐1 family as targets for inflammatory disease

“…In this capacity, IL‐18 is recognized as a Th1 response inducing factor alongside IL‐12, and indeed requires the presence of IL‐12 to elicit this function. As well as enhancing IFNγ expression from CD 4+ T cells, IL‐18 can also work in concert with IL‐12 to drive NK cell effector function and expression of IFNγ, and induce NK cell expansion through enhanced IL‐2 sensitivity . IL‐18 induces such responses through stimulating a unique heterodimeric receptor consisting of IL‐18Rα ligand binding and IL‐18Rβ accessory chains.…”