Table 1 Cytokines and their general main functions for immunity and inflammation. List of cytokines tested from saliva based on cellular mechanism pathways influenced on or by the cytokine. Pathways include Th1/Th2 cellular maturation and effects, Th9/Th17/Th22/Treg cellular maturation and effects, inflammatory cytokines, chemokines, and growth factors. Includes descriptions of their general functions for immunity and inflammation. Many of these analytes are detectable in saliva, especially when testing in diseased patients
From: Natural and induced immune responses in oral cavity and saliva
Biological Functions | Presence in Saliva | |
|---|---|---|
Th1/Th2 | Relating to the stimulation CD4+ cells to mature into Th1 or Th2 cells; or downstream effects of their activation [60] | |
GM-CSF | Hematopoietic growth factor and immune modulator; proangiogenic, proinflammatory cytokines; produced by variety of cell types and tissue types, induced by IL- 1, IL- 6, and TNF-α [61, 62] | Yes |
IFN-γ | Effector molecule in macrophage and inflammatory activation, important in inherent immunity, specifically tumor control, viral infection, and intracellular bacteria [63] | Yes |
IL- 1β | Pro-inflammatory cytokine released upon activation of inflammasome; Immune cell recruitment and activation, modulates adaptive immunity [61, 64] | Yes |
IL- 2 | Non-specific antigen proliferative factor for T lymphocytes, regulating inflammation and tumors; during inflammation, secretes pro-inflammatory cytokines IL- 1, TNF-α, and TNF-β [65, 66] | Yes |
IL- 4 | Immunomodulatory cytokine in adaptive immunity; activates B and T cells, humoral immune response, and reduces pathological inflammation [63] | Yes |
IL- 5 | Driver of maturation and maintenance of eosinophils and antibody secreting B cells; implication in mast cells of asthmatic airways-lung and saliva axis [67, 68] | Yes |
IL- 6 | Pleiotropic cytokine influencing antigen-specific immune responses and pro-inflammatory reactions [61, 67] | Yes |
IL- 8 | Pro-inflammatory cytokine regulating PMN activity, inducing chemotaxis, cellular shape change respiratory burst, and inducing adhesion of PMN to endothelial cells [69, 70] | Yes |
IL- 12p70 | Cytokine produced by immune cells in response to antigenic stimulation; stimulates growth and function of T cells; associated with autoimmune and inflammatory conditions [66, 71] | Yes |
IL- 13 | Anti-inflammatory cytokine implicated in muscle metabolism mediation, cancer invasion, and progression of paracrine and autocrine signaling in tumor microenvironments [72] | Yes |
IL- 18 | Proinflammatory cytokine that regulates autoimmune and inflammatory diseases; signals to CD4 T cells; also implicated in generating and activating Th17 cells [73] | Yes |
TNF-α | Inflammatory cytokine that activates endothelial and fibroblast cell, leading to upregulation of adhesion molecules; upregulation is implicated in periodontitis [61, 74] | Yes |
Th9/Th17/Th22/Treg | Relating to the stimulation CD4+ cells to mature into Th9, Th17, Th22 or Treg cells; or downstream effects of their activation [75] | |
IL- 9 | Pleiotropic cytokine with pro-allergic inflammation capabilities, immunity mechanisms against extracellular parasites [76] | Yes |
IL- 10 | Anti-inflammatory cytokine released to suppress activation of IL- 6, IL- 1, and TNF-α [77] | Yes |
IL- 17 A (CTLA- 8) | Pro-inflammatory cytokine to activate B cells and macrophages for antibody and more pro-inflammatory signaling; activate various non-immune cells to produce antimicrobials; mediates occurrence/development of chronic immune-mediated inflammatory diseases [78, 79] | Yes |
IL- 21 | Pleiotropic pro-inflammatory cytokine targeting broad range of immune cells and exaggerates host-immune response; suppresses Th2 differentiation/development and anti-inflammatory IL- 13 [80] | Yes |
IL- 22 | Regulates mucosal responses to invasion and damage, promoting tissue repair and supporting epithelial growth and health [81] | Yes |
IL- 23 | Important for Th17 cell survival and maintenance; acts as bridge between nonspecific and specific immunity [82] | Yes |
IL- 27 | Potentially pro- and anti-inflammatory; induces development of Th1 and T follicular helper (Tfh); inhibit differentiation of Th2 and Th17 cells; promote virus-specific CD4 T cells [83] | Yes |
Inflammatory Cytokines | Cytokines involved in immune regulation and inflammation, either promoting or inhibiting inflammation [84] | |
IFN-α | Antiviral cytokines produced in response to viral infection; can modulate genes encoded for proteins for inflammation, apoptosis, and other immune responses [85, 86] | No |
IL- 1-α | Pro-inflammatory cytokine similar to IL- 1β but exists in homeostatic environments preformed; can act as an alarmin, dual function intra and extracellularly to promote inflammation [87, 88] | Epithelial and endothelial cells, parotid saliva |
IL- 1RA | Anti-inflammatory by competitive inhibition with IL- 1 onto the IL- 1 receptors [88, 89] | Yes |
IL- 7 | Non-hematopoietic-derived cytokine that plays an essential role in supporting normal T cell development and homeostasis; upregulation enhances effector T cell response and is associated with autoimmune disorders [90] | Yes |
IL- 15 | Induces proliferation of natural killer cells and cytotoxicity, participation in early innate immune cytokine response [91] | Yes |
IL- 31 | Pleiotropic cytokine mainly implicated in pruritus and other itchy skin conditions; also implicated in pathogenesis of allergic inflammation in the airways [92, 93] | Oral mucosa |
TNF-ß | Pro- and anti-inflammatory capabilities; initiating early immune response but can inhibit proliferation and cytokine production functions, even promote apoptosis [94, 95] | Yes |
Chemokines | Chemokines involved mainly in migration of cells and maintaining homeostasis of the immune system [96] | |
Eotaxin (CCL11) | Protein to stimulate eosinophils and recruit them to inflammatory sites; implicated in CNS [97] | No |
GRO-α (CXCL1) | Chemotactic for neutrophils, angiogenesis in cutaneous wound healing, oral keratinocytes proliferation and migration increase with stimulation from other cytokines [98] | Yes |
IP- 10 (CXCL10) | Stimulated by cytokine upregulation, specifically IFN-γ; induces variety of effects specifically in cell growth and development (tumor regulation, promotion, and angiostatins) [99] | Yes |
MCP- 1 (CCL2) | Monocyte chemoattractant protein upregulated in inflammatory conditions; relational with other MCPs and MIPs to influence type and magnitude of immune response [100] | Yes |
MIP- 1-α(CCL3) | Chemotactic secreted by macrophages to recruit inflammatory cells, promote wound healing, inhibition of stem cells, and maintains effector immune response; important in bone resorption [101] | Yes |
MIP- 1-ß (CCL4) | Lymphocyte attractants, augmenters for T lymphocyte adhesion to VCAM- 1, induce monocyte chemotaxis, calcium mobilization, and exocytosis; immature dendritic attractants [102] | Yes |
RANTES (CCL5) | CC-chemokine for migration and metastasis of human cancer cells (oral); contribute to neuronal function and metabolic disorders [103] | Yes |
SDF- 1-α | Produced by fibroblasts, responsible for bone marrow progenitor cell movement and transendothelial leukocyte migration; tissue remodeling; implicated in periodontitis and neutrophil migration [104] | Yes |
Growth Factors | Secreted, biologically active molecules affecting cell growth, mitosis, or differentiation [105] | |
BDNF | In neurotrophins family; can induce cellular apoptosis in pro-form and cell development, differentiation, survival, and plasticity in mature form [106] | Variable |
EGF | Epidermal growth factor for epithelial regeneration after physical and chemical aggression [107] | Yes |
FGF- 2 | Fibroblast growth factor is a neurotrophic protein associated in protection against depression, anxiety, and stress [108] | Yes |
HGF | Endogenous growth substance produced by all cells of mesenchymal origin, important in regulating embryogenesis, morphogenesis, and mitogenesis; ability to repair and regenerate damaged tissues [109] | Yes |
NGF-β | Nerve growth factor majorly produced by cells in oral tissues, secreted into saliva, for oral wound healing [110] | Yes |
PDGF-BB | Exogenous platelet-derived GF that mediates epithelial-mesenchymal interactions; inflammation and tissue injury causes stimulation of proliferation and migration of certain cells to mucosal fibroblasts [111] | Yes |
PIGF- 1 | Placental GF within vascular endothelial GF family; supports growth and differentiation of trophoblasts, released by many cells upon stimulation and closely connected to placental or maternal biological activity [112] | Yes |
SCF | Salivary conditioning film forms on all surfaces of mouth, acting as interface between components of the mouth (tongue, oral mucosa, enamel); plays role in lubricating oral cavity [113] | Yes |
VEGF-A | Vascular endothelial GF that is crucial for maintenance of mucous membrane homeostasis and can accelerate wound healing in oral cavity; induces angiogenesis, increases microvascular permeability [114, 115] | Yes |
VEGF-D | Can be secreted into saliva, regulates lymphangiogenesis; can bind to receptors on lymphatic endothelial cells and stimulate their proliferation and migration [116] | Yes |