Table 1.
Effect of cytokines on NK cells and ADCC effects.
| Cytokine | Function | Main mechanism | Ref. |
|---|---|---|---|
| IL2 | Activation | IL2 ex vivo treatment of NK cells can restore the impairment of ADCC, concomitant to the normalization of the expression of CD16 zeta molecules. Serum cytokine profiling demonstrated an increase in IFN-γ induced protein 10. Gene expression analysis revealed significant changes in a highly restricted set of genes, including forkhead box P3, IL-2 receptor antagonist, and CISH. | (73, 74) |
| IL-15 | Activation | IL15 is a novel cytokine that activates NK cells through components of the IL-2 receptor. IL-15 was associated with increased expression of NK cell activation markers NKp46 and NKG2D and increased NK cell isolated ADCC activity, whereas inhibitory receptors PD-1 and Tim3 were reduced. | (75, 76) |
| IL-2/IL-15 | Activation | IL-2 combined with IL-15 enhanced the expression of NKG2D receptor to inhibit Wilms’ tumor via the mitogen-activated protein kinase (MAPK) signaling pathway. | (77) |
| CX3CL1 | Activation | CX3CL1 overexpression recruited NK cells and increased NK cell-mediated cytotoxicity in HER-2 positive breast cancer. | (78) |
| IL-23 | Activation | IL-23-induced NK cell activation and stimulated IFN-γ production by CD56bright NK cells, which involved MEK1/MEK2, c-Jun N-terminal kinase, and phosphatidylinositol-3 kinase pathways. | (79) |
| IL-21 | Activation | IL-21-treated NK cells secreted high levels of IFN-γ, which enhanced NK cell activation through extracellular signal-regulated kinase and signal transducer and activator of transcription (STAT) 1 signaling pathway, thus inhibiting tumor growth. | (80) |
| TGF-β | Inhibition | TGF-β inhibited the production of IFN-γ in human NK cells and ADCC, and these effects were mediated through SMAD3. | (81, 82) |
| IL-1R8 | Inhibition | The high concentrations of IFN-γ, TNF-α, GM-CSF, CCL3, and CXCL8 release were observed in NK cells with IL-1R8 transient silencing by electroporated siRNA. | (83) |
| IL-12 | Activation | IL-12 is an essential cytokine involved in the generation of memory-like NK cells, and IL-12 combined with anti-TGF-β can increase the maturation of tumor-associated NK cells. | (84) |
| CISH | Inhibition | CISH is a key negative regulator of IL-15 signaling in NK cells, and it inhibits anti-tumor activity of human NK cell. | (85) |