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Page 10 of 23 Monks et al. J Cancer Metastasis Treat 2019;5:24 I http://dx.doi.org/10.20517/2394-4722.2018.79

Table 2. Effect of APN on the immune system
Anti-inflammatory effects
Monocytes Inducing anti-inflammatory cytokine; IL-10 [127] , IL-1RA [127]
Macrophages 1. Inducing anti-inflammatory cytokines; IL-10 [127-138] , IL-1RA [127] , IL-4 [130]
2. Suppressing pro-inflammatory cytokines; IL-1β [128] , IL-6 [131,132] , TNF-α [128,130,137-139]
3. Less cellular infiltration in disease models [128,140]
4. Down-regulating chemokine; IP10/CXCL10 [141] , I-TAC/CXCL11 [141] , Mig/CXCL9 [141] , CCL18
5. Inducing mannose receptors [128]
6. Clearing early apoptotic cells via CRT pathway [2]
7. Inhibiting MMP-12 [142] or inducing TIMP-1 due to IL-10 effect (independent of MMP-9 inhibition) [135]
8. Inducing type 1 arginase [128] , HO-1 [130]
9. Suppressing scavenger receptors; MSR-AI [132] , class A [139]
10. Inhibiting TF [143]
11. Suppressing cellular maturation [144]
Dendritic cells 1. Inducing anti-inflammatory cytokine; IL-10 [127,145] & IL-1RA [127]
2. Attenuating pro-inflammatory cytokine; IL-1β [145] , IL-8 [145] , IL-12p40 [145,146] , INF-g [145] , TNF-α [145]
3. Inhibiting positive co-stimulator (CD80 [145,146] , CD86 [145,146] , CD40 [145] )
4. Down-regulating HLA II [145,146]
5. Up-regulating negative co-stimulator (PD1-PDL1 [146] )
6. Inhibiting ROS [145]
7. Suppressing cellular maturation [145,146]
Endothelial cells 1. Inhibiting adhesion molecule, ICAM-1 (CD54) [147] , E-selectin [148] , sVEGFR1 [148]
2. Attenuating infiltration of immune cells into disease models [141,149]
3. Inhibiting apoptosis [18,150]
4. Suppressing pro-inflammatory cytokine; TNF-α [18,151] , IL-6 [148,152] , IL-8 [153]
5. Promoting EPC function & localisation [154]
Natural killer cells Down-regulating TRAIL [155] & Fas Ligand [155]
T cells 1. Inhibiting antigen-specific T cell proliferation [145,146,156]
2. Inhibiting pro-inflammatory cytokine; IL-1β [145] , IL-2 [156] , IL-8 [145] , TNF-α [156] , IFN-g [145,156]
3. Inducing T cell apoptosis [156]
4. Less cellular infiltration in disease models [141,149]
5. Promoting Th2 differentiation [145]
Regulatory T cells 1. Inducing expansion of Treg [146]
2. Inducing T cell anergy [145]
B cells Inhibiting B lymphopoiesis [157]
Liver cells 1. Inducing anti-inflammatory cytokine, IL-10 [130] , IL-4 [130]
2. Inhibiting pro-inflammatory cytokines, TNF-α [130,140] , IL-1β [140] , IL-6 [140] , CCL-2 [140] , CXCL10 [140] , ICAM-1 [140]
3. Alleviating apoptosis [140]
Pro-inflammatory effects
Macrophages Only inducing transient TNF-α [132,133,138] , IL-6 [132] (subsequently suppressed by IL-10) or IL-6 (via IRS2 through
unidentified APN receptor [158]
Dendritic cells 1. Promoting positive co-stimulators; CD86 [159] *, CD40 [159] *
2. Up-regulating HLA II [159] *
3. Inducing pro-inflammatory cytokines, IL-12 [159] *, IL-6 [159] *, IL-1β [159] *, IL-23 [159]*
*(APN suboptimal)
T cells 1. Activating T cells via induction of INF-g [160] *, IL-6 [160] *
2. Promoting Th1 & Th17 differentiation [159] *
*(APN suboptimal)
Liver cells Inducing pro-inflammatory chemokine, CXCL8 [161]
Fibroblasts Inducing pro-inflammatory cytokines; IL-6 [162,163] **
**(flAcrp + suboptimal)

This table summarizes the controversies surrounding the role of APN on the immune system. On balance, majorities of work support
the role of APN regulating the immune system negatively. However, the caveats associated with the ability of APN to stimulating the
immune system are also demonstrated (as per discussed in the text). The body of evidence on this area tends pale into insignificance
comparing to the large experimental data supporting the notion of APN as an immune modulator. IRS-2: insulin receptor substrate-2;
ROS: radical oxygen species; C/EBPα: CCAAT/enhancer binding protein-alpha; MCP-1: monocyte chemoattractant protein-1; EPC:
endothelial progenitor cell; eNOS: endothelial nitric oxide synthase; IP-10: interferon (IFN)-inducible protein-10; I-TAC: IFN-inducible T
cell alpha chemoattractant; Mig: monokine induced by IFNg, M1 markers (TNF-α, IL-6, MCP-1), CRT/CD91; CRT: calrecticulin; HO-1: heme
oxygenase-1; TF: tissue factor; Treg: regulatory T cells

Despite STAT3 being recognised as the dominant mediator for IL-10 functions, this pathway can mediate
anti-inflammatory effects in an IL-10 independent manner [166] . This includes downstream activation of ETS
family transcriptional repressor, ETV3 and a helicase family corepressor, Strawberry notch homologue 2
(SBNO2) that can inhibit NF-κB activation [167] .