|
| Cytokines | Major secretory cells | Effect of cytokines in uveitis | Regulatory effect of natural product components |
|
| IL-1 | Macrophages, epithelial cells | IL-1 can promote the activation of CD4 + T cells and the expression of IL-2 receptor 2 and the antigen presentation ability of APC such as monocyte macrophage [10]. Synergized with IL-2 or interferon, IL-1 can enhance NK cell activity. Moreover, it can recruit neutrophils and promote the release of inflammatory mediators [99]. Intravitreal injection of recombinant IL-1 receptor antagonist anakina (ANA) can inhibit the increase of laser-induced neovascularization choroidal area in a concentration-dependent manner and improve the uveitis symptoms such as iris edema, adhesion, atrophy, and neovascularization [100]. | Matrine ↓ Berberine ↓
TWP ↓
APS ↓
HPS ↓
RP ↓
Curcumin ↓ |
| IL-2 | T cells | Il-2 can stimulate the proliferation and differentiation of Th17 cells, activate NK cells, and macrophages [101]. | |
| IL-4 | T cells, mast cells | IL-4 can induce the initial T cells to differentiate into Th2 cells and participate in the humoral immune response. Moreover, it can promote the proliferation and differentiation of activated B cells and induce immunoglobulin E (IgE) antibodies’ production [102, 103]. | TGP ↑ |
| IL-6 | T cells, macrophages, endothelial cells | IL-6 mediates the differentiation of Th1 to Th17 cells and inhibits physiological intraocular T cell apoptosis [104]. Intravitreal injection of anti-IL-6 (MP5-20F3) twice significantly relieved experimental autoimmune uveitis in mice [105]. | Matrine ↓
Berberine ↓
TWP ↓
HPS ↓
Curcumin ↓ |
| IL-8 | Monocytes, macrophages, endothelial cells, fibroblasts, T cells | IL-8 takes part in chemotactic signals to recruit leukocytes, leading to directional migration and exocytosis of stored proteins [106, 107]. Intravitreal injection of IL-8 (100 ng) can induce uveitis in the rabbit [108]. Anti-IL-8 antibody treatment partially treated EIU in rabbits [109]. Gene polymorphisms of IL-8 may lead to different susceptibility to ocular Behcet’s disease OBD and increase the risk of developing the disease [110]. IL-8 was found to be the best marker for the diagnosis of children’s idiopathic anterior uveitis [111]. | Berberine ↓
Curcumin ↓ |
| IL-10 | Monocytes | IL-10 can inhibit the expression of major histocompatibility complex (MHC) and costimulatory molecules in APC and inhibit the production of cytokines by activated Th1 cells [76]. IL-10 polymorphisms +434 T/C, +504G/T, and -2849C/T are predisposing factors for uveitis in children [112]. | TWP ↓
HPS ↑
RP ↓ |
| IL-12 | Macrophages, dendritic cells | IL-12 can stimulate T cells and NK cells to produce IFN-γ and promote CD4 + helper T cells to differentiate into Th1 cells that produce IFN-γ [113]. | |
| IL-17 | Th17 cells, NK cells, CD8 T cells, neutrophils | As a proinflammatory cytokine, IL-17 can recruit and activate neutrophils and has synergistic effects with TNF, IL-1β, IFN-γ, granulocyte-macrophage colony stimulating factor (GM-CSF), and IL-22 [114, 115]. | Berberine ↓
RP ↓
Curcumin ↓ |
| IL-18 | Activated macrophages | Interleukin-12 and interleukin-18 synergically promote the production of interleukin-17A and interleukin-17F, which is independent on IL-23 [116]. IL-18 was found to be a good biomarker for monitoring activity and regression of uveitis [117]. | |
| IL-21 | Th2 cells | IL-21 promotes the differentiation of Th17 cells that participate in the pathogenesis of autoimmune diseases such as scleritis, uveitis, and Behcet’s disease [118]. Also, it can promote the proliferation and differentiation of B cells, NK cells, and effector CD8 + T cells [119, 120]. | Berberine ↓
TWP ↓ |
| IL-23 | Macrophages, dendritic cells | IL-23 participates in the occurrence, recurrence, and chronicity of uveitis by promoting the production of IL-17. Moreover, it takes part in the recruitment and differentiation of myeloid cells, which is considered an upstream pathway in intermediate uveitis pathogenesis [121]. | Berberine ↓
TWP ↓
Curcumin ↓ |
| IL-27 | Macrophages, dendritic cells, monocytes | IL-27 promotes the differentiation of Th1 but inhibits the proliferation of Th2, Th17, and Treg cells [109]. | |
| IL-32 | NK cells, macrophages, monocytes, and T lymphocytes, epithelial cells, endothelial cells, mesenchymal stromal cells, fibroblasts, and hepatocytes | IL-32 can induce proinflammatory cytokines like TNF-α, IL-8, and IL-1β and induce anti-inflammatory cytokines like IL-10 [122]. Moreover, it can mediate the differentiation of monocytes into dendritic cells [123]. | |
| IL-33 | Endothelial cells, smooth muscle cells | Both IL-33 and IL-33R were expressed in RPE cells, IL-33 can inhibit the production of IFN-γ, and IL-17 promote Th2 to secrete cytokines and significantly reduce the severity of EAU mice [124, 125]. | |
| IL-35 | Regulatory T cells | IL-35 can significantly increase the expression of IL-10 and TGF-β and decrease the expression of INF-γ, IL-12, and IL-17 [126]. Moreover, it can promote Treg cells’ proliferation and inhibit the proliferation of Th17 cells [127]. | |
| IL-37 | Epithelial cells, dendritic cells, monocytes | IL-37 significantly inhibits IL-1β, IL-6, IL-10, IL-21, IL-23, TNF-α, and IFN-γ. IL-37 has a significant positive correlation with disease activity of HLA-B27 associated acute anterior uveitis (AAU) [61] as well as chronic primary angle-closure glaucoma [128]. | TWP ↓ |
| TNF-α | Macrophages, T cells, NK cells | TNF-α can directly kill cells infected by virus, activate monocyte macrophages, and enhance their phagocytic and bactericidal ability. Moreover, TNF-α can promote antigen processing and presentation pathways and increase Th1 and Th17 cytokines level [129]. Adalimumab and infliximab have become the most widely used biological agents in the treatment of noninfectious uveitis [130]. TGF-β can induce the differentiation of Th0 towards Treg and inhibit the differentiation of Th17 cells at high concentrations. At low concentrations, with the presence of IL-6, it can induce Th0 to differentiate into Th17 [131]. In patients with uveitis, the expression of TGF-β in aqueous humor decreases, which is considered a potential factor to promote uveitis. Similar changes are observed in the aqueous humor of patients with Vogt Koyanagi Harada during the active phase [132]. Adalimumab and infliximab have become the most widely used biological agents in the treatment of non- infectious uveitis [133]. | Matrine ↓
TWP ↓
APS ↓
HPS ↓
RP ↓
Curcumin ↓ |
| TGF-β | Monocytes, T cells, chondrocytes | TGF-β can induce the differentiation of Th0 towards Treg and inhibit the differentiation of Th17 cells at high concentrations. At low concentrations, with the presence of IL-6, it can induce Th0 differentiate into Th17 [131]. In patients with uveitis, the expression of TGF-β in aqueous humor decreases, which is considered a potential factor in promoting the development of uveitis. Similar changes are observed in the aqueous humor of patients with Vogt Koyanagi Harada during the active phase [132]. | Berberine ↓ |
| IFN-γ | T cells, NK cells | It can activate macrophages, promote MHC expression and antigen presentation, promote Th1 differentiation, and inhibit Th2 differentiation [133]. IFN-γ can induce VEGF expression in retinal cells through PI-3 K/Akt/mTOR/p70S6 kinase pathway [134]. Deficiency in IFN-gamma can inhibit the development of uveitis induced by muramyl dipeptide [133]. | TGP ↓
TWP ↓
RP ↓ |
| VEGF | Tumor cells | VEGF can not only promote the increase of vascular permeability and the degeneration of the extracellular matrix but also promote the neovascularization of choroid, iris, and retina, leading to severe visual loss, even blindness. | Matrine ↓
Curcumin ↓ |
| MCP-1 | Immature DC cells, monocytes/macrophages, T cells, NK cells | MCP-1 can recruit immature DC cells, T cells, and monocytes/macrophages to participate in immune response and inflammatory response. Alteration of MCP-1 in aqueous humor was associated with glaucoma secondary to Fuchs uveitis syndrome [8, 135]. | Berberine ↓
TWP ↓ |
| MMP-9 | Neutrophils, monocytes/macrophages | MMP-9 can remodel the dynamic balance of the extracellular matrix and promote the release of TGF-β1 and VEGF [136]. MMP-9 levels peak at the most severe uveitis stage and then return to baseline as the inflammation subsides [136]. | TWP ↓ |
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