Table 2.
Cytokines released after surgery promoted the mobilization and enhanced the function of MDSCs
| Cytokines | Name | Biological function in MDSCs | Biological function in surgery |
|---|---|---|---|
| Interleukins | IL-6 | IL-6 potentially expands peripheral MDSCs;53 major cytokine among IL-6 family cytokines responsible for STAT3 activation and premetastatic niche54 | Main proinflammatory cytokine responds to surgery and the magnitude of IL-6 elevation correlates with the extent of surgical trauma severity; the elevation of IL-6 associated with postoperative adverse outcome55,84 |
| IL-8 | Attracts MDSCs and elicits extrusion of neutrophil extracellular traps56 | Proinflammatory cytokine responds to surgical stress57 | |
| Colony-stimulating factors (CSF) | GM-CSF | Recruit and expand MDSCs, promote migration and differentiation of MDSCs58 | GM-CSF ameliorates microvascular barrier integrity via pericyte-derived Ang-1 during wound healing59 |
| G-CSF | Mobilize G-MDSCs to the lung pre-metastatic niche60 | Angiogenic circulating factor responding to surgery61 | |
| Chemokines | CXCL1 | Recruits CXCR2-positive MDSCs to form a premetastatic niche, promoting liver metastases62 | Proangiogenic chemokine, that participate wound healing |
| CCL2 | CCL2/CCR2 axis is important for MDSC recruitment63 | Evaluation of CCL2 help guide postsurgical management for clear-cell renal cell carcinoma patients64 | |
| SDF-1/CXCL 12 | SDF-1/CXCR4-mediated recruitment of MDSCs from bone marrow65 | Chemokine, involving wound healing66 | |
| Growth factors | VEGF | Activate NF-κB signals, producing CXCL1 to recruit CXCR2+ MDSC62 | One of the most potent proangiogenic factors during wounds healing67 |
| Interferon | IFN-γ | IFN-γ significantly upregulated iNOS expression in M-MDSCs68 | Mediating postoperative proinflammatory responses69 |
| Tumor necrosis factor (TNF) | TNF-α | Cytokine attracting neutrophils and monocytes to pre-metastatic niche; Signaling of TNF-R2 promoted MDSC survival through upregulation of c-FLIP and inhibition of caspase-8 activity70 | First cytokine responding to injury, trigger an inflammatory cascade. Endogenous wound TNF-α down-regulates collagen synthesis during normal wound healing71 |
| Transforming growth factor (TGF) | TGF-β | Factor secreted by MDSCs, that with strong immunosuppressive function166 | TGF-β exhibits two postoperative peaks of secretion at 2 h and 3–4 days. Stimulates angiogenesis and fibroblast proliferation72 |
| Extracellular matrix | MMP9 | MMP-9-cleaved OPN fragment, OPN-32 kDa, was responsible for MDSCs expansion73 | Serum MMP-9 increased significantly 4 days after surgery and was still high 30 days after surgery; play a role in normal tissue remodeling events74 |
| LOX | Promote the ECM remodeling to recruit MDSC75 | A key enzyme required for crosslinking and deposition of insoluble collagen, and targeting LOX might be an approach to reduce adhesions76 | |
| Fibronectin | Fibronectin is a large glycoprotein capable of interacting with various ECM molecules produced by a variety of cell types and involved in cell attachment and chemotaxis79 | ECM derived DAMPs after surgery that activate inflammation and monocyte activation; also participated in wound healing80 | |
| DAMPs | S100A8/9 | S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in premetastatic lung tissue77,78 | Causing neutrophil migration to inflammatory sites; a biomarker of postoperative organ injury85 |
| Prostaglandin-endoperoxide synthase | COX-2 | Catalyzed the synthesis of PGE-2, which exacerbated the immunosuppressive activity of MDSC81 | An enzyme responsible for the production of PGs that respond to surgical stress82 |