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.

IL‑18 knockout alleviates atopic dermatitis‑like skin lesions induced by MC903 in a mouse model

“…Generally, IL-18 is involved in the phosphorylation of STAT3 and promotes cell proliferation (26,27). However, the present study demonstrated IL-18 KO did not affect STAT3 expression in the process of AD-like lesions.…”

IL‑18 knockout alleviates atopic dermatitis‑like skin lesions induced by MC903 in a mouse model

“…Generally, IL-18 is involved in the phosphorylation of STAT3 and promotes cell proliferation (26,27). However, the present study demonstrated IL-18 KO did not affect STAT3 expression in the process of AD-like lesions.…”

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.…”

Molecular Mechanisms of IL18 in Disease

“…Additionally, administration of recombinant ERDR1 augmented the cytotoxicity of primary human NK cells against leukemia cancer cells [39]. IL18 in combination with IL2 induces NK cells and has a cytotoxic role against cancers [13]. Consistent with other research [32], our microarray analysis showed that Erdr1 expression was increased in liver, BAT, and brain of Il18 −/− mice, implying that Erdr1 and Il18 negatively regulate each other.…”

IL‑18 knockout alleviates atopic dermatitis‑like skin lesions induced by MC903 in a mouse model

“…Generally, IL-18 is involved in the phosphorylation of STAT3 and promotes cell proliferation (26,27). However, the present study demonstrated IL-18 KO did not affect STAT3 expression in the process of AD-like lesions.…”

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.…”

Molecular Mechanisms of IL18 in Disease

“…Additionally, administration of recombinant ERDR1 augmented the cytotoxicity of primary human NK cells against leukemia cancer cells [39]. IL18 in combination with IL2 induces NK cells and has a cytotoxic role against cancers [13]. Consistent with other research [32], our microarray analysis showed that Erdr1 expression was increased in liver, BAT, and brain of Il18 −/− mice, implying that Erdr1 and Il18 negatively regulate each other.…”

IL‑18 knockout alleviates atopic dermatitis‑like skin lesions induced by MC903 in a mouse model

“…Generally, IL-18 is involved in the phosphorylation of STAT3 and promotes cell proliferation (26,27). However, the present study demonstrated IL-18 KO did not affect STAT3 expression in the process of AD-like lesions.…”

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.…”

Molecular Mechanisms of IL18 in Disease

“…Additionally, administration of recombinant ERDR1 augmented the cytotoxicity of primary human NK cells against leukemia cancer cells [39]. IL18 in combination with IL2 induces NK cells and has a cytotoxic role against cancers [13]. Consistent with other research [32], our microarray analysis showed that Erdr1 expression was increased in liver, BAT, and brain of Il18 −/− mice, implying that Erdr1 and Il18 negatively regulate each other.…”