Table 1.
Pro- and anti-inflammatory cytokines in RA.
| Cytokines | Sources | Affected cells | Types | Major functions |
|---|---|---|---|---|
| Proinflammatory | ||||
| TNF-α | Fibroblast, endothelial cell, and macrophage | Synoviocyte, chondrocyte, osteoclast, and endothelial cell | None | Promotes pannus tissue formation; synovial inflammation; synthesis of MMPs, PGE2, and collagenase; vasospasm, joint destruction; osteoclastogenesis; and bone resorption [61]. |
| IFN-γ | NK cell, T cell, macrophage, B cell, and dendritic cell | T cell, B cell, macrophage, endothelial cell, and APC | None | Activates antigen-presenting cells, upregulates the expression of MIC molecules on monocytes, and aggravates the local inflammatory responses in RA. |
| IL-1 | Fibroblast, macrophage, endothelial cell, synovial cell, and chondrocyte | Synovial cell, macrophage, neutrophil, B cell, T cell, osteoclast, synaptic cell, and chondrocyte | IL-1α, IL-1β, IL-18, IL-1, F5-10, and IL-33 | Promotes TNF-α and IL-6 production, vasospasm, synaptic cell and chondrocyte synthesis, release of PGE2, secretion of MMPs, proliferation of synovial cells, and osteoclast differentiation and activity. Acts synergistically with TNF-α to damage the cartilage. |
| IL-2 | T cell, monocyte, dendritic cell, and synovial cell | T cell, B cell, macrophage, and NK cell | None | Activates and maintains T cell differentiation and proliferation, mediates phosphorylation of STAT5, and triggers active transcription in Treg cells [12]. |
| IL-6 | Osteoblast, stromal cell, T cell, B cell, fibroblast, endothelial cell, monocyte, and keratinocyte | Th17 cell, B cell, osteoclast, macrophage, neutrophil, and synoviocyte | None | Regulates osteoclast formation and bone resorption, promotes proliferation and differentiation of activated B cells, enhances the effects of IL-1 and TNF-α, maintains differentiation and homeostasis of Th17 cells, triggers synthesis of acute-phase proteins, and induces synovial neovascularization. |
| IL-8 | Monocyte, FLS, macrophage, synoviocyte, synovial lining cell, and endothelial cell | Neutrophil, NK cell, T cell, synovial cell, chondrocyte, and macrophage | None | Chemotactic and activation factor for neutrophils, stimulates NK and T cells to express γ-interferon and FasL, respectively, promotes apoptosis of T and B cells, stimulates synovial cells, and chondrocytes to produce NO, PGE2, MMPs, TNF-α, and IL-6. |
| IL-15 | Macrophage, fibroblast, endothelial cell, dendritic cell, myocyte, epithelial cell, and astrocyte | CD4+ and CD8+ T cell, monocyte, macrophage, and NK cell | None | Promotes the accumulation and activation of T cells into the joints; secretion of other cytokines (TNF-α), adhesion molecules, proteases, and monocyte chemotactic factors (MCP-1 and IL-8); and expression of IL-17 and MMPs (MMP-1 and MMP3). It is associated with bone destruction and secretion of RF in RA [62]. |
| IL-17 | CD4+ Th17 cell, NK cell, neutrophil, eosinophil, monocyte, and mast cell | T cell, fibroblast, synovial cell, macrophage, neutrophil, osteoclast, synaptic cell, chondrocyte, endothelial cell, and epithelial cell | IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F | By binding to IL-17RA/RC receptors, stimulates production of TNF-α, IL-1β, IL-6, IL-8, IL-23, chemokines, nitric oxide, prostaglandins, GM-CSF, and MMPs; promotes RANKL expression, NF-κB activation, and vasospasm formation; activates osteoblasts and osteoclasts by regulating the RANKL/RANK/OPG signaling pathway; and inhibits the synthesis of proteoglycans and collagen [63]. |
| IL-18 | Macrophage, synoviocyte | Th1 cell, chondrocyte, synovial cell | None | Promotes expression of mononuclear factors and TNF-α. |
| IL-23 | Macrophage, dendritic cell, and B cell, | T cell, dendritic cell, and macrophage | None | Induces formation and differentiation of Th17 cells, differentiation of osteoclasts, e production of IL-6, TNF-α, IL-1β, and chemokines (CXCL-1, GCP-2, and CXCL-8). |
|
| ||||
| Anti-inflammatory | ||||
| IFN-α | Leukocyte, dendritic cell | T cell, monocyte, macrophage, NK cell, synoviocyte, and B cell | None | Inhibits synthesis of collagen, expression of MHC antigens, proliferation of B cells, release of prostaglandins from monocytes, and bone resorption and disrupts the balance between collagen and fibronectin. |
| IFN-β | FLS, macrophage, dendritic cell, and osteoclast | T cell, dendritic cell, macrophage, NK cell, fibroblast, and osteoclast | None | Reduces the production of TNF-α, IL-1β, and IL-6 and increases the secretion of IL-1Rα and IL-10, modulates signaling molecules involved in the NF-κB pathway, and inhibits osteoclastogenesis and the negative feedback pathway of c-fos [64]. |
| IL-1Ra | Monocyte, macrophage, neutrophil, epithelial cell, and fibroblast | Monocyte, macrophage, lymphocyte, epithelial cell, and fibroblast | None | Abolishes IL-1 activation. |
| IL-4 | Th2 cell, mast cell, basophil, and dendritic cell | B cell, T cell, macrophage, dendritic cell, chondrocyte, FLS, osteoclast, and APC | None | Inhibits the production of MMPs, IL-1β, IL-6, IL-8, IL-12, IL-17, and TNF-α and promotes the production of IL-1Rα and soluble TNF receptors, directs B cells to produce antibodies like lgG1 and lgE, and promotes the expansion of Th2 cells and adhesion of macrophages to vascular endothelial cells [65]. |
| IL-10 | Th2 cell, B cell, macrophage, mast cell, monocyte, synovial cell, and chondrocyte | B cell, Th1 cell, macrophage, APC, and monocyte | None | Inhibits the expression of MHC class II antigens, proliferation of Th1 and B cells, and production of IFN-γ, TNF-α, IL-1, lL-3, GM-CSF, COX-2, and MMPs and promotes the production of IL-1Rα, soluble tumor necrosis factor receptor, and TIMPs. |
| IL-13 | B cell, T cell, and macrophage | B cell, monocyte, and endothelial cell | None | Inhibits ADCC and production of inflammatory cytokines (IL-1, IL-6, IL-8, and TNF-α), induces expression of IL-1Ra, and promotes B cell differentiation and antibody synthesis. |
| IL-25 (also called as IL-17E) | Th17 cell, Th2 cell, mast cell, epithelial cell, and macrophage | Th17 cell, NK cell, type 2 myeloid cell, Th9 cell, basophil, eosinophil, mast cell, endothelial cell, macrophage, dendritic cell, and CD4+ T cell | None | Inhibits IL-17A and IFN-γ production and induces the expression of various chemokines and cytokines (IL-4, IL-5, and IL-13). Expression of IL-25 in articular cartilage inhibits the synthesis of cartilage and bone stimulates the release of NO and IL-6 production. |
|
| ||||
| Cytokine with dual effects | ||||
| TGF-β | FLS, macrophage, monocyte, NK cell, and T cell | Fibroblast, epithelial cell, Th17 cell, Treg cell, and macrophage | None | Proinflammatory: chemotactic to fibroblasts, promotes fibroblast proliferation, epithelial cell differentiation, and the stability of Th17 cells. |
| Anti-inflammatory: in the absence of IL-6, promotes the differentiation and proliferation of Treg cells and inhibits activation of IFN-γ, TNF-α, macrophages, and antibody production. | ||||
Abbreviations: ADCC: antibody-dependent cellular cytotoxicity; APC: antigen-presenting cells; COX-2: cyclooxygenase-2; CXCL: chemokine (C-X-C motif) ligand; FLS: fibroblast-like synoviocytes; GCP-2: granulocyte chemotactic protein-2; GM-CSF: granulocyte-macrophage colony-stimulating factor; IFN: interferon; MHC: major histocompatibility complex; MCP-1: monocyte chemoattractant protein-1; MIC: macrophage inhibitory cytokine; MMP: matrix metalloproteinase; NO: nitric oxide; OPG: osteoprotegerin; PGE2: prostaglandin E2; RANK: receptor activator of nuclear factor-κB; RANKL: receptor activator of nuclear factor kappa Β ligand; TIMP: tissue inhibitors of metalloproteinase; TNF: tumor necrosis factor.