Table 1 ILs related to pancreatic carcinogenesis
Interleukins | Source (not exhaustive) | Receptor | Inflammatory impact | Effect on immune response | Mechanism in pancreatic carcinogenesis | Refs |
|---|---|---|---|---|---|---|
IL-1 superfamily: IL-1 subfamily | ||||||
IL-1α | Keratinocytes, epithelial cells, cells from the entire gastrointestinal tract, brain astrocytes, myeloid cells | IL-1R1 IL-1R3 sIL-1R3 | ↕ | General function ➀ Extensive regulation of immune response, differentiation, and activation of myelomonocytic cells, function of Tregs ➁ Maintenance of homeostasis and pathogenesis of diseases and cancer Cancer immunity ➀ TH17 polarization ➁ Recruitment of MDSCs, TAMs and TANs ➂ T-cell activation via the production of IL-2 and IL-2R | Activation of NF-κB signaling and CAFs to maintain inflammatory TME | 28,246,364,394,491,492,493,494,495,496,497,498,499,500,501,502,503,504,505 |
IL-1β | Myeloid cells | IL-1R2 IL-1R3 sIL-1R2 sIL-1R3 | ↓ | ➀ Increased infiltration of immunosuppressive macrophages and MDSCs ➁ Enhanced angiogenesis ➂ Prolonged cell survival ➃ Activation of quiescent PSCs and suppression of antitumor immunity via TLR4 signaling and NLRP3 inflammasome ➄ Dysregulated autophagy and increased ER stress | ||
IL-33 | Endothelial, epithelial, and fibroblast-like cells | IL-1R3-IL-1R4 sIL-1R4 | ↓ | ➀ Stimulation of myeloid and lymphoid cells supporting their proliferation, survival, migration, and production of type 2 immune mediators (IL-5 and IL-13) ➁ Direction of DC-mediated TH2 cell polarization ➂ Supporting type 1 responses dominated by TNF and IFNγ | Driver of early-stage neoplasia via chromatin switching following tissue damage | |
IL-2 (common γ-chain) family | ||||||
IL-4 | Epithelial cells, CD4+ T cells, basophils, eosinophils, mast cells, macrophages, DCs, NK cells, NKT cells | IL-4Rα-γc IL-4Rα-IL-13Rα1 | ↓ | ➀ Differentiation of naïve CD4 T cells into TH2 cells ➁ Ig class switch to IgG1 and IgE in B cells ➂ Alternative macrophage activation | ➀ Activation of c-Jun, ERK-1/2, and STAT3 signaling ➁ Promoted cell growth and survival via decreased apoptosis | |
IL-3 family | ||||||
IL-5 | T cells (mainly TH2 cells), eosinophils, mast cells, ILCs | IL-5Rα-βc | ↑ | ➀ Chemotaxis and activation of the integrin CD11b and prolonging eosinophil survival ➁ Antibody secretion and class switching of B cells | Enhanced pancreatic tumor motility through STAT5 activation | |
IL-6 family | ||||||
IL-6 | Immune and nonimmune cells | Classic: IL-6Rα-gp130 Trans: sIL-6Rα-gp130 | ↓ | Regulation of innate and adaptive immunity via B-cell stimulation and regulation of the balance between Tregs and effector T cells | ➀ Activation of STAT1, STAT3, MAPK, and PI3K signaling and other oncogenic pathways ➁ Increased cell proliferation and decreased apoptosis ➂ Dysregulated autophagy | |
IL-10 family | ||||||
IL-22 | CD4+ helper T cells, CD8+ cytotoxic T cells, γδ T cells, ILCs | IL-22Rα1-IL-10Rβ IL-22Rα2 (IL-22BP) | ↓ | Regulation of innate and adaptive immunity and tissue homeostasis both locally and systemically | ➀ Activation of STAT1, STAT3, STAT5 and NF-κB, MAPK, and PI3K/Akt/mTOR signaling pathways ➁ Promoted cell proliferation and survival, ADM, and the EMT and stemness of precancerous cells | |
IL-12 family | ||||||
IL-35 | CD4+Foxp3+ Tregs, Bregs, DCs, active endothelial and muscle cells, monocytes | IL-12Rβ2-gp130 IL-12Rβ2-IL-12Rβ2 gp130-gp130 IL-27Rα-IL-12Rβ2 | ↓ | ➀ T-cell proliferation and expansion↓ ➁ TH17 cell differentiation↓ ➂ Number of TH cells in humoral immunity↓ ➃ Expansion and activation of Tregs↑ ➄ Expression of IFNs↑ ➅ Transformation of B cells into IL‐35‐producing Bregs | Stimulated cell proliferation and diminished immune response through the production of IL-10, IL-35, and activation of BTK signaling | |
IL-17 family | ||||||
IL-17A/F | TH17 cells, CD8+ T cells, γδ T cells, NKT cells, ILCs | IL-17RA–IL-17RC | ↑ | Host defense against bacterial and fungal pathogens | ➀ Promotion of neoplastic cell transformation, PanIN formation and progression ➁ Activation of CAFs ➂ Cancer cell stemness↑ ➃ Increased cell growth and decreased cell death through activation of the gp130-JAK2-STAT3-dependent pathway during ADM | |
IL-17B | Intestinal and pancreatic cells | IL-17RB | ↕ | ➀ Enhanced inflammatory response via neutrophil migration ➁ Anti-inflammatory effect via blocked IL-25 signaling | ||
IL-17C | Epithelial cells | IL-17RA-IL-17RE | ↑ | Protection against microbial infection and pathogenesis of autoimmune disease | ||
IL-17D | Resting CD4+ T cells, CD19+ B cells, T cells, smooth muscle cells, epithelial cells | Unknown | ↑ | ➀ Classic proinflammatory-cytokine responses ➁ Tumor and viral surveillance mediated by NK cells | ||
IL-17E (IL-25) | CD4+ cells, CD8+ T cells, macrophages, DCs, mast cells, eosinophils, epithelial cells | IL-17RA-IL-17RB | ↓ | Type 2 immunity and host defense against helminth and parasitic infections via production of anti-inflammatory cytokines such as IL-4, IL-5, and IL-13 for eosinophil recruitment | ||
Other ILs | ||||||
IL-8 (CXCL8) | Endothelial cells, fibroblasts, keratinocytes, synovial cells, chondrocytes, infiltrating neutrophils, TAMs, T cells | CXCR1 CXCR2 ACKR1/DARC | ↑ | Recruitment of neutrophils and MDSCs | Promotion of cell growth, survival, and angiogenesis | |
IL-13 | CD4+ T cells, basophils, eosinophils, mast cells, macrophages, DCs, NK cells, NKT cells | IL-13Rα1-IL-4Rα IL-13Rα2 | ↓ | ➀ Suppressing the production of proinflammatory cytokines ➁ Enhancing major histocompatibility complex class II and CD23 on monocytes ➂ Induction of anti-CD40-dependent IgG class switching ➃ Promoting IgG and IgM synthesis in B cells | ➀ Detrimental polarization of TAMs in ADM/PanIN lesions ➁ Exacerbated pancreatic fibrosis via the release of IL-1Rα and CCL2 | |
