Table 1 The principal cytokines, playing a role in IBD and CRC [35,36,37,38,39,40,41,42,43]
From: Colorectal carcinoma in the course of inflammatory bowel diseases
Cytokine | Function in IBD | Function in CRC/CAC |
|---|---|---|
Cytokines with pro-tumorigenic role | ||
 IL-1β | Promotes IBD. Enhances the transcription and expression of IL-6 during the activation of cytokine cascade. | Mediates cancer-related inflammation and can be secreted by immune, stromal and tumor cells. Induces tumor cells proliferation, promotes the recruitment of myeloid-derived suppressor cells (MDSCs) to tumors, which supports cancer progression and induces the activation of the Wnt signaling pathway. |
 IL-4 | Stimulates IgE class-switch recombination in B cells. Induces Th2 differentiation and IL-13 expression. Signals via STAT6. | May have distinct functions, depending on the tumor environment. Overexpress in early stages of CRC, appears to drive tumor development. |
 IL-6 | Regulates inflammation by triggering a consolidated phase through monocyte recruitment. | Plays a formative role in the process of the chronic cancer-related inflammation, which becomes a genuine component of the tumor and the associated systemic reaction. |
 IL-8 | Activates immune responses. Plays as a key mediator of immune tolerance. | Overexpressed in tumor tissue. Promotes tumor growth, metastasis and chemoresistance. Activates the Akt and MAPK pathways and promote the expression of genes responsible for cell proliferation, invasion and angiogenesis. |
 IL-17A | Necessary for intestinal homeostasis in IBD. Stabilizes epithelial barrier function. Induces pro-inflammatory cytokine/chemokine expression in endothelial cells; affect NF-κB-dependent signaling. | IL-17A serum levels are elevated in CRC patients. Positively correlates with tumor size or circulating tumor cells and poor survival. Indirectly activates STAT3 through IL-6. Activates the NF-κB pathway in CRC cells, thereby driving tumor survival and growth. Promotes the inflammation in CRC. |
 IL-22 | Induces the production of antimicrobial peptides and mucus by epithelial cells. Drives intestinal inflammation. | Promotes tumor formation in bacterial driven colitis model. High levels of IL-22 in the serum or CRC tissue are predictive of a poor survival. Promotes resistance to chemotherapy. Promotes CRC development via induction of stemness in tumor cells. |
 IL-23 | Suppress IL-10 in IBD intestinal mucosa and promotes chronic inflammation. Activates proliferation and cytokine expression in pathogenic Th17 cells; acts on STAT3-dependent signaling. | Induces the CRC. Overexpressed in primary CRC tissue. High IL-23 levels in primary tumor tissue are predictive of a higher rate of CRC metastasis. Indirectly promotes tumor cell survival. |
 IL-33 | Promotes Treg-mediated control of colonic inflammation. Positively correlates with the extent of inflammation. | May promote or inhibit CRC development. Overexpressed in intestinal adenomas and adenocarcinomas in CRC patients. Indirectly affects the proliferation of tumor cells, decreasing the barrier function of the intestine, what allows for increased translocation of bacterial products to normally sterile tissues and induces the production of pro-tumorigenic cytokines, such as IL-6, by immune cells. Triggers the production of pro-angiogenic factors, which may promote CRC progression and metastasis. |
 TNF-α | Drives inflammation: regulates immune cell survival and function. Signals via NF-κB and MAPK pathways. | Links inflammation and cancer. In CRC, it is produced mainly by activated macrophages. Overexpressed in CRC tissues. TNF-α serum levels positively correlates with CRC progression and reduced patient survival. Promotes cell survival and CRC development. Contribution of TNF-α to CRC may be determined by the timing of its secretion during tumorigenesis or the type of the immune cells secreting it. |
 TGF-β | Inhibits cell growth and activation. | May function as a potent tumor suppressor that induces cell cycle arrest in early tumors, but high TGF-β levels in the primary tumor or serum correlates with poor survival. Promotes IL-11 secretion by CAFs, which in turn activates STAT3 and drives the proliferation of tumor cells. |
Cytokines inhibiting CRC development | ||
 IL-12 | Stimulates Th1 differentiation and effector cytokine production (IFN-γ, TNF-α). Functions via STAT4-dependent signaling. | Plays a central role both for the induction and the expansion of Th1 responses as well as the activation of cytotoxic immune effectors, such as NK and CD8+ T cells. Activates and induces IFN-γ production, which limits tumor growth and metastasis. High preoperative IL-12p40 serum levels predicted a better survival in CRC patients. |
 IL-15 | Activates NK cells development | Regulates anti-tumor cytotoxicity and modulates the inflammatory tumor microenvironment. |
 IL-17F | Blockade of IL-17F ameliorates the inflammation in colitis. | In contrast to IL-17A it does not lead to the activation of NF-κB in CRC cells. |
 IL-18 | Activates the inflammation. | Restricts inflammation in the intestine by limiting the differentiation of Th17 cells and promoting the expression of effector molecules in Treg. Participates in the repair of the intestinal epithelium, possibly via IL-22. Promotes protective host immunity mediated by cytotoxic cells, including CD8+ T lymphocytes and NK cells. |
 NF-κB | Activation of NF-κB is strongly induced in the inflamed gut of IBD patients. Correlates with the severity of intestinal inflammation. | Activates the transcription of target genes that influence cellular proliferation, migration and inflammation. Cancer cells exhibit aberrant constitutive NF-kB activation, which is involved in multiple signaling cascades related to carcinogenesis. |
Cytokines with unclear contribution to CRC | ||
 IL-9 | Impairs mucosal wound healing. Regulates epithelial cell proliferation and barrier function. Acts on STAT3/STAT1/MAPK-dependent signaling. | Possibly promotes lymphomagenesis but also may inhibit the tumor growth by promoting anti-tumor immunity. |
 IL-10 | Inhibits antigen presenting cells and pro-inflammatory cytokine expression by immune cells. Activates STAT3-dependent signaling. | Binding to its receptor activates STAT1, STAT3, and STAT5. In CRC patient, IL-10 serum levels increase over time during tumor progression. High preoperative serum levels of IL-10 correlate with poor survival of CRC patients. |
 IL-21 | Growth and differentiation factor for germinal center B cells. Induces the activation of JAK1, JAK3, and mainly STAT1/STAT3. | Upregulated in patients with ulcerative colitis-associated colon cancer. May impact on the polarization of the T helper cell response in CRC. Its expression in human tumor positively correlates with disease-free survival. |
 GM-CSF | Promotes antigen presentation and maintains T cell homeostasis. | Overexpressed in primary colon tumors. Activates the JAK-STAT, the MAPK, and the PI3K pathways, which results in cell survival and proliferation. |