Names Aliases | Cells that secrete the cytokine/chemokine, receptors they bind to, and their effects after SCI |
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IL-1α IL-1F1 | Released via activated microglia and PDMs largely in response to disease, infection, or inflammatory events [52] Binds to IL-1R1 [52] Required for neutrophil recruitment during cell death-induced sterile inflammation [128] |
IL-1β IL-1F2 | Produced by activated microglia and PDMs as a proprotein, which is proteolytically processed to its active form by caspase 1 (CASP1/ICE) [52, 129,130,131] Binds to the IL-1R [129] Plays a more substantial role than IL-1α post-SCI [52, 132, 133] Stimulates inflammatory mediators including prostaglandins, cyclooxygenase 2, and phospholipase A2 [52, 129] |
IL-2 | Produced by activated T-cells [134] Binds to IL-2R complex, which consists of IL-2Rα, IL-2Rβ, and the common γ-chain subunits [134] Contributes to the proliferation of T-helpers [87] Responsible for initiating the proper response of memory T-cells to invading pathogens [135] |
IL-4 | Produced by T-helper cells, eosinophils, basophils, and mast cells [136] Binds to IL-4Rɑ, which will either dimerize with the common cytokine-receptor γ-chain and produce the type-1 signaling complex, or with IL-13Rα1 and produce the type-2 signaling complex [136, 53] Increases microglia/macrophages expressing antigens characteristic of an anti-inflammatory M2 phenotype [70] Increases the number of oligodendrocytes and neuronal markers βIII-tubulin and NeuN after SCI, suggesting a role in neuroprotection [137] |
IL-5 | Produced by hematopoietic and non-hematopoietic cells, including granulocytes, T-cells, and natural helper cells [138] Binds to IL-5R and stimulates B-cell growth as well as increases immunoglobulin secretion (primarily IgA). Is also a key mediator in eosinophil activation [139, 140] |
IL-6 | Expressed in astrocytes, microglia and PDMs, and neurons [37] Binds to IL-6R, which exists either as a membrane-bound receptor or a soluble receptor [141] Activates inflammation and is a strong recruiter of immune cells after SCI [142] Acts on neural stem cells to induce their differentiation into astrocytes [143] |
IL-8 CXCL8 GRO (the rat analogue) | Produced by a wide variety of cells including monocytes, endothelial cells, T-cells, and macrophages [144] Binds to CXCR1 and CXCR2 receptors [52] Induces chemotaxis in neutrophils and granulocytes [52] Upregulated for at least 14Â days after SCI and strongly correlates with the extent of injury [87, 49, 38, 14] |
IL-10 | Produced by monocytes, B-cells, dendritic cells, natural killer cells, and T-cells [145] Binds to IL-10R heterotetramer complex made of two IL-10R1 molecules and two IL-10R2 molecules [146] Downregulates several pro-inflammatory cytokines and inflammatory species [56] Provides trophic support to neurons through downregulation of pro-apoptotic factors and upregulation of anti-apoptotic factors [56] |
IL-12 IL-12ɑ P35 | Produced by dendritic cells, macrophages, monocytes, neutrophils, microglia cells, and B-cells [147] Binds to IL-12R, which consists of the IL-12Rβ1 and IL-12Rβ2 chains [148] IL-12(p70) expresses nitric oxide synthase and TNFα in microglia and PDMs [149] |
IL-13 | Produced by T-cells, dendritic cells, and activated Th2 cells [150] Binds either to IL-13Rɑ1 or IL-13Rɑ2 [53, 151] Involved in the production of transforming growth factor beta (TGF-β) [151] |
IL-17É‘ IL-17 CTLA-8 | Produced by several types of cells including T-cells, dendritic cells, and macrophages [152] Binds to the A and C subunits of IL-17R [152] IL-17 knockout mice showed increased locomotor function after SCI suggesting a role in regulating secondary degeneration of neural tissue [153] |
TNF-ɑ TNF TNFSF2 | Produced by microglia, PDMs, astrocytes, oligodendrocytes, monocytes, and neurons [37, 39] Two active forms are transmembrane TNFɑ and soluble TNFɑ [154] Soluble TNFα is released by regulated cleavage of transmembrane TNFɑ by TNFɑ-converting enzyme (TACE/ADAM17) [154] Binds to TNFR1 and TNFR2 [154] Affects cell proliferation, differentiation, apoptosis, immunity, and inflammation [37] Recruits macrophages to injury site [37] |
IFN-γ | Produced by γẟ T-cells and leads to the activation of macrophages [95, 155] Induces secretion of IL-10 from microglia and PDMs [155] Can act synergistically with GM-CSF to promote the production of cytokines [156] |
GM-CSF CSF2 | Produced by macrophages, mast cells, T-cells, fibroblasts, and endothelial cells in response to immune activation and cytokines that mediate inflammation [157] Causes differentiation of hematopoietic progenitor cells into granulocytes, macrophages, and dendritic cells [158] Can stimulate the proliferation of bone marrow stem cells and reduce leukocyte apoptosis, as well as cause microglia to proliferate and change their morphology [158] GM-CSF-induced activation of microglia may promote functional recovery and axonal regeneration by release of brain-derived neurotrophic factor or by phagocytosis of myelin debris [159, 160] |
MCP-1 CCL2 | Secreted by activated T-cells, astrocytes, microglia, and monocytes [161] Binds to CCR2 [106] Activates and recruits mononuclear phagocytes, T-cells, and B-cells [162] |
MIP-1ɑ CCL3 | Secreted by activated T-cells, astrocytes, microglia, and monocytes [161] Promotes chemotaxis of monocytes and T-cells [161] Expression induced by pro-inflammatory stimulators, such as LPS, TNFα and IL-1β, and neuronal injury [163] Can enhance the production of other pro-inflammatory cytokines via CCR1, CCR4, and CCR5 [163] Impacts CNS inflammation through regulation of macrophages and astrocytes [163] |
RANTES CCL5 TCP228 | Produced by astrocytes and is primarily involved in promoting migration of M2 macrophages [51] Expression induced by IL-1 and macrophage migration inhibitory factor [51] Binds to CCR1, CCR3, and CCR5 [164] Associated with T-cell activation in SCI. Chronic T-cell activation subsequently contributes to neurodegeneration and inhibits repair of injured tissues [165] Induces the migration and recruitment of a wide variety of cells including T-cells, dendritic cells, natural killer cells, eosinophils, basophils, mast cells, and endothelial progenitor cells [51] May help amplify inflammatory response by facilitating the recruitment of inflammatory cells to the injury [51] |
TGF-β1 | Produced by lymphocytes, macrophages, and dendritic cells [166] Binds to TGF-βR1, TGF-βR2, and TGF-βR3 [167] Activates glial cells and phagocytes to form connective tissue and extracellular matrix [168] Influences the differentiation, proliferation, and state of activation of leukocytes [166] Known to suppress expression of MHC class II antigen [166] |