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. 2023 Feb 16;24(4):4002. doi: 10.3390/ijms24044002

Table 1.

Main sources, target cells, receptor types, activated pathways, and functions of each cytokine.

Source Targets Action Receptors Pathways Functions
Leptin Adipose cells, enterocytes, CAFs, some cancer cells Adipose cells, epithelial cancer cells, cancer stem cells, immune cells, endothelial cells, potentially fibroblasts Endocrine, paracrine, and autocrine ObR

  • JAK2/STAT3;

  • MAPK/ERK;

  • PI3K/Akt/Rac [34,35].

  • Regulates the energy balance, suppressing food intake, controlling appetite and body weight [36,37];

  • Increases cancer and immune cell proliferation, anti-apoptosis, migration, invasion, angiogenesis [38], EMT [39] and cytokine secretion [40].
TNFα Adipocytes, macrophages, CD8+ T, CD4+ Th1, NK cells, mast cells, fibroblasts, osteoclasts, endothelial, DCs, Th17, TAMs, epithelial, and malignant cancer cells [41,42,43,44] Epithelial cancer cells, cancer cells, immune cells, endothelial cells, potentially fibroblasts Endocrine, paracrine, and autocrine TNFR1/TNFR2

  • NF-κB [45,46], JNK, MAPKs, AKT, AP-1, TAZ, JNK/P38 (activate AP-1);

  • Non-canonical NF-κB [47];

  • MAPK/ERK.

  • Up-regulates transcription of pro-inflammatory genes, including anti-apoptotic proteins, cell-adhesion molecules, inflammatory cytokines, and chemokines [48,49];

  • Activates cell survival and proliferation, VEGF production, angiogenesis [50,51], and cell migration;

  • Cancer cell survival and/or proliferation [52], tumor-promoting, aggressiveness [53], EMT, MMP9 expression;

  • IL-17 production by Th17 cells [53].
IL1-β Macrophages, adipocytes, monocyte, DCs, fibroblasts, B-cells, TAMs [54,55], and some cancer cells [54,56] Cancer cells, Th cells, B cells, NK cells, γδT cells, macrophages, endothelial cells [57]. Paracrine and autocrine CD121a/IL1R1, CD121b/IL1R2

  • NF-κB, STAT1, PI3K/Rac [58];

  • (ERK)1/2, AP-1 [59].

  • Increases COX-2 expression in cancer cells for cancer progression [60,61] and regulates maturation and proliferation of B cells, activation of NK [62];

  • Can activate Th, neutrophils to dampen the CD8+ T cells [63], γδT and Th17;

  • Induces migration/invasion [64,65], EMT [66], angiogenesis (viaVEGF, neo-angiogenesis, CXCL2) [67,68], and matrix-remodeling activities [69,70].
IL-6 Monocytes, macrophages, TAM [71,72], T cells, B cells, fibroblasts, CAFs [73,74], endothelial cells, and adipocytes [75,76,77] some cancer cells [78,79], myeloid-derived suppressor cells (MDSC), and CD4+ T cells Activated B, DCs, cells, T cells, CD4+ T, plasma cells, hematopoietic stem cells, cancer cells, macrophages, and endothelial cells [80] Endocrine, paracrine, and autocrine IL-6Rα/gp80 IR6Rβ/grp130

  • JAK1, JAK2, and Tyk2 [81];

  • STAT3/STAT1 [82,83];

  • SHP2, ERK, MAPK PI3K [84,85] and mTOR.

  • Mediates tumorigenesis, increasing cell-cycle progression, resistance to apoptosis and senescence [86], tumor cell proliferation, survival [87,88], and metastasis [89,90];

  • Blocks DC differentiation, thereby preventing T cell activation and inducing T cell death [91], Th17 cells [92];

  • Promotes the mobilization of anti-tumor CD8+ effector T cell responses, the development of APC, such as DCs and cytotoxic T cells [91,93], as well as the survival, proliferation, differentiation, and recruitment of leukocytes [94,95].
IL-8/CXCL8 Macrophages [96], TAMs [97], monocytes [98], fibroblasts [99], epithelial cells [100], vascular endothelial cells [101], CAFs [102], T cells, and some cancer cells Macrophages, TAMs, monocytes, fibroblasts, endothelial cells, CAFs, T cells, neutrophils [103,104], and some cancer cells [105] Paracrine and autocrine CXCR1/IL8RA, CXCR2/IL8RB

  • PI3K [106], PKB/Akt [106], MAPK [103,104];

  • Raf-1/MEP/ERK1 cascade, p38 MAPK [107] and PLC;

  • FAK [108,109], STAT3 [97,110], JAK2/STAT3/Snail [96];

  • Ras/MAPK/PI3K [111,112], NF-κB/VEGF activation [113].

  • Activates cell survival, angiogenesis, and cell migration [114], cell motility, invasion, and metastasis [115];

  • Induces M2/TAM macrophage polarization [116] and alters NK cell function [117], EMT [118], and chemoresistance [101], suppresses CD8+ T-cell activity [119] and limits the anti-PD-1 immune response.

  • Induces of inflammatory cells recruitment to exert cytotoxic activities [120]
IL-23 DCs, phagocytic cells, monocytes, neutrophils, and innate lymphoid cells (ILCs) [121,122,123] T cells, NK, NKT cells, tumor cells, monocytes, macrophages, and DCs [124] Paracrine and autocrine IL23R

  • TYK2/JAK2/STAT3 [124,125];

  • NFκB.

  • Regulates Th17 cell differentiation, stimulates IL-17 production, maintains suppressive Treg activity;

  • Decreases the infiltration of CD4+ and CD8+ T cells [126];

  • Enhances tumor-associated inflammation, tumor growth, metastasis [127], angiogenesis [128,129], immunosuppressive cytokines [126];

  • Increases the expression of VEGF, MMP9, CD31, and the proliferative marker Ki67 in tumors.
IL-17A T helper 17 cells (Th17) [130,131], T-cells [132], CD8+ T cells, γδ T cells, and NKT, NK Epithelial cells, endothelial cells, cancer cells, CD4-CD8- T cells, other T-cells [132], fibroblasts, keratinocytes, and macrophages Paracrine and autocrine IL-17R IL17RA/IL17RB

  • ERK1/2 phosphorylation, p38/MAPK and STAT3;

  • NF-κB.

  • Amplifies the inflammatory response, the secretion of inflammatory cytokines, including IL-6, TNFα, and IL-1β;

  • Enhances the production of chemokines, such as CXCL-8 which leads to granulocyte recruitment at inflamed sites;

  • Activates oncogenic signal transducer, tumor growth [133], migration [134], tissue invasion, tumorigenesis, inhibits apoptosis, and angiogenesis.
IL-12 DCs, B cells, T cells, and macrophages T cells, NK cells, NKT cells, monocytes, macrophages, DCs, CD4+ T cells, and cancer cells Paracrine and autocrine IL-12Rβ1IL-12Rβ2

  • JAK2 and TYK2 [135], STAT4.

  • Activates M1 macrophage polarization and enhances anti-tumor cytotoxic immune responses in tumor microenvironment [135];

  • Regulates Th1 cell differentiation and cytokine secretion including IFN-γ;

  • Upregulates MHCI on tumor cells to facilitate antigen presentation;

  • Activates Th1, recruits cytotoxic T cells, NK, and CD8+ T cells;

  • Activates the differentiation of naïve CD8+ T cells to the effector phenotype and acts as an anti-apoptotic factor.
IL-2 Th1-cells, CD4+ T, CD8+ T cells [136], activated DCs and NK cells [137,138], NK [139], B [140], T [141] cells, neutrophils [142], and some tumor cells [143] B cells, NK cells, macrophages, CD4+ and CD8+ T cells, mature DCs, endothelial cells [144,145,146], Tregs, NK cells, and tumor cells Paracrine and autocrine IL-2Rα (CD25)IL-2Rβ (CD122)IL-2Rγ (CD132)

  • JAK1 and JAK3, STAT5A/STAT5B STAT1 and STAT3;

  • PI3K-AKT, JAK-STAT, and MAPK/ERK.

  • Differentiates CD4+ T cells into Th1 and Th2 [147], promotes CD8+ T cells, inhibits Th17 differentiation but also expands Th17 cells [148];

  • Increases NK cytolytic activity, mediates activation-induced cell death, induces development of Treg (FoxP3) and cytotoxic T cells (CD8+ T cells);

  • Activates [149] tumor cell growth, survival, and differentiation, cytokine production (Il-4, Il-12,Il-6) [150,151], and activates induced cell death in diverse immune cell types [152,153].
IFN-γ NK and NKT in innate immunity, macrophages, epithelial cells, Th1 [154], DCs [155], Tγδ [156], and CD8+ T cells [157,158] in the adaptive immune response [159] T-cells and NK, cancer cells, macrophages, Treg, endothelial cells, Tγδ [156], CD4+ T, and CD8+ T cells [157,158] Endocrine, paracrine, and autocrine IFNGR1/2

  • JAK(1/2)-STAT(1/3/4) [160,161];

  • JAK-STAT;

  • MAP, PI3K, JNK, and NF-κB [162,163,164];

  • Src kinases/MAPKs/ERK/p38/then Fos and Jun kinases;

  • ICAM1-PI3K-Akt-Notch1.

  • Implicated in allergies [165,166], obesity [167], autoimmune diseases [168], and cancer;

  • Activates the proinflammatory response [169] by promoting NK cell activity [170], differentiation of naïve CD4+ T-cells into Th1 and Th2 cells [171], increases the killing capacity of CD8+ T-cells [172] and decreases the proliferation of Tregs [173];

  • Eliminates tumors [154], reduces metastasis by up-regulating fibronectin [155], arrests the cell cycle and initiates apoptosis in tumor cells, inhibits the migration of TAMs;

  • May enhance tumor cell survival, induces risk of metastasis, EMT transcription factors [174,175];

  • May induce apoptosis in CD4+ T-cells, suppress immune and secondary antitumor immune response [176], causes immune evasion adaptive immune resistance to immune checkpoint therapy [177].
IL-10 Th2, Th1, Treg [178], Th17, and also by CD8+ T cells, monocytes, macrophages, DCs [179], B cells [180], mast cells, eosinophils [181], keratinocytes, epithelial cells, and even some tumor cells [182,183] DCs [184], T, B, NK, Treg, mast, dendritic cells, M2/TAM lymphocytes, and cancer cells458 Endocrine, paracrine, and autocrine Two IL-10R1 and two IL-10R2

  • Jak1 and Tyk2;

  • STAT3/STAT1/STAT5;

  • MAPK inhibition and/or activation of a PI3K/AKT inhibitory pathway.

  • Leads to the expression of anti-inflammatory mediators that block various inflammatory pathways;

  • Regulating intestinal inflammation, tumor immunosuppression, viral infection, allergic reactions [185];

  • Inhibits the production of proinflammatory cytokines, such as IL-1β, IL-6, IL-8, IL-12, IL-18, CSF, and TNF-α) [186], suppresses Th1-associated cytokines (IL-2, IFN-γ, and stimulates B cell and NK cell survival and proliferation, as well as their production of antibodies and cytokines [187];

  • Downregulates the expression of co-stimulatory molecules on macrophages, differentiation, and maturation of DCs, activation of CD4+ T cells [188,189];

  • Inhibits NF-κB translocation;

  • Contributes to tumor growth and promotion (STAT3 in cancer cells), angiogenesis, and metastasis. In carcinomas, IL-10 levels increase TGF-β excretion in Treg cells and macrophages and then promote EMT [190];

  • Suppresses T-cell proliferation and activity in breast cancer [191] and inhibits T-cell-stimulated anti-tumor immunity by down-regulating MHC class II (APC) and class I (colon tumor cells) [192].