By Levi Clancy for Student Reader on
Cytokines (aka monokines or lymphokines) are regulatory proteins which bind specific receptors and have pleiotropic (multiple) or redundant functions.
Cytokines are important for: activation, such as stimulation proliferation of activated T cells; recruitment signals, such as brining cells to sites of inflammation; and differentiation, such as of lymphocytes in the thymus and bone marrow. There are three pathways in which cytokines operate: autocrine, where cells self-stimulate; paracrine, where cells interact with nearby cells; endocrine, where cells circulate to interact with far-away tissues.
Some cytokines are classified as chemokines. A chemokine is a small peptide released in response to injury or infection, with similarities to the antigen-binding domains of the major histocompatibility complex. Chemokines are released by macrophages, endothelial cells, keratinocytes, smooth muscle and T cells.
There are two kinds of chemokines: α chemokines, with a region bearing contiguous cysteins; and β chemokines, with conserved cysteins separated by another amino acid.
α chemokines include MCAF, RANTES and MIP-1β β chemokines include IL-8 and SDF-1. Phagocytic cells and T cells migrate towards concentrations of chemokines, following a chemokine gradient. Also, certain chemokines have multiple roles in fetal development. In addition, chemokine receptors for RANTES, MIP-1&alpha, MIP-1β and SDF-1 are accessory receptors for entry of HIV into a cell.
|Interleukin 1 (IL-1)||Mφs, DCs & B Cells||Innate||A lymphocyte activator, IL-1 is an endogenous pyrogen (causing fever) which works on TH and B cells to: co-stimulate activation, promoting response to antigens; stimulate differentiation and clonal expansion; and stimulate endothelial expression of adhesion molecules.|
|Interleukin 2 (IL-2)||TH1 Cells||Adaptive||A lymphocyte activator, IL-2 is a (sometimes autocrine) stimulator of natural killer cell and activated T cell proliferation.|
|Interleukin 3 (IL-3)||Eosinophil maturation, activation and proliferation. Granulocyte and macrophage proliferation and colonies.|
|Interleukin 4 (IL-4)||TH2 & Mast Cells||Adaptive||A macrophage activator, IL-4 stimulates phagocytic activity and MHC class II gene expression. IL-4 stimulates isotype switching by activating the promoters for Iε, and Iγ1 (the I regions for ε and γ1 heavy chain constant region genes). IL-4 is pivotal in regulating the IgE response: IgG1 and IgE account ∼2% of all antibodies secreted by splenic B cells incubated with LPS; IgG1 accounts for ∼50% and IgE accounts for ∼20% of all antibodies secreted by B cells incubated with LPS and IL-4. IL-4 knockout mice cannot mount an IgE response to parasites. Also, CD4 T cells activated in presence of IL-4 develop into TH2 cells (especially if IL-6 is also present); IL-4 and IL-10 both inhibit T cell differentiation into TH1 cells.|
|Interleukin 5 (IL-5)||TH2 Cells||Adaptive||Eosinophil maturation, activation and generation.|
|Interleukin 6 (IL-6)||Adaptive||CD4 T cells activated in presence of IL-4 develop into TH2 cells (especially if IL-6 is also present); IL-4 and IL-10 both inhibit CD4 T cell differentiation into TH1 cells.|
|Interleukin 8 (IL-8)||An inflammatory cytokine, IL-8 stimulates inflammation and has a key role in cell migration. IL-8 alters adhesion molecules on monocytes, increasing their affinity for the endothelial adhesion protein ICAM-1. Binding to ICAM-1 helps monocytes migrate through tissues to the site of infection.|
|Interleukin 10 (IL-10)||TH2 Cells||A macrophage activator, IL-10 inhibits cytokine production and down-regulates MHC class II gene expression. IL-4, IL-10 and TGF-β all inhibit CD4 T cell differentiation into TH1 cells.|
|Interleukin 12 (IL-12)||Macrophages & DCs||Innate||CD4 T cells differentiate into TH1 cells in presence of IL-12 and IFN-γ (also, IFN-γ inhibits CD4 T cell differentiation into TH2 cells). IL-12 and IFN-γ are produced by macrophages and NK cells.|
|Interleukin 13 (IL-13)||Like IL-4, IL-13 stimulates IgE production.|
|Interferon Alpha||Granulocytes||Innate||Interferon Alphas (IFNα) are a family of 14 closely related small proteins synthesized by granulocytes in response to a viral infection.|
|Interferon Beta||Fibroblasts & others||Innate||Interferon Betas (IFNβ) are produced by most cells of the body in response to double-stranded RNA (dsRNA indicates that a virus is present). IFNβ activates endoribonuclease (which cleaves viral RNA) and proteins inhibiting translation (thus stopping viral replication). Also, IFN-β promotes isotype switching to IgA by activating the promoter for Iα and Iγ2b (the I regions for the the IgA and IgG2b heavy chain constant region genes).|
|Interferon Gamma||TH1, CD8+ & NKs||Adaptive||Interferon Gammas (IFNγ) activate macrophages, and increase antigen presentation by stimulating expression of Class I and II MHC molecules. IFN-γ also activates isotype switching to IgG2a by activating the promoter for Iγ2a (the I region for the IgG2a heavy chain constant region gene). In addition, CD4 T cells differentiate into TH1 cells in presence of IL-12 and IFN-γ -- also, IFN-γ inhibits CD4 T cell differentiation into TH2 cells, so TH1 activation amplifies itself. IL-12 and IFN-γ are produced by macrophages and NK cells, and are both absolutely critical for clearing intracellular infections (knockouts for either die from intracellular infections). IFN-γ inhibits the DNA rearrangement required to isotype switch to IgE.|
|MCAF||Macrophage chemoattractant and activating factor (MCAF) is self-explanatory.|
|MIP-1β is a chemoattractant for CD8+ cells.|
|RANTES||T cells||RANTES attracts memory CD4+ cells (aka TH cells or helper T cells).|
|SDF-1||Attracts cells to stromal elements.|
|TGF-β||Adaptive||Transforming Growth Factor Beta (TGF-β) inhibits B and T cell proliferation, and T cell and macrophage function. Along with IL-10, TGF-β inhibits activation and growth of TH1 cells -- since IL-10 and TGF-β are secreted by TH2 cells, this aids amplification of TH2 cell populations.|
|TNF-α||Innate||An inflammatory cytokine along with IL-8, tumor necrosis factor alpha (TNF-α, aka cachectin) stimulates: inflammation (heat, swelling, immunoglobulin accumulation, complement, capillary permeability and capillary widening); and expression of genes encoding adhesion molecules (thus helping recruit immune system cells to the site of inflammation).|
|Erythropoietin||Erythropoietin induces differentiation of hematopoietic cells toward red blood cells.|
|G-CSF||G-CSF induces formation of granulocyte colonies.|
|M-CSF||TH1 & TH2 Cells||M-CSF induces formation of macrophage colonies.|
|GM-CSF||GM-CSF induces formation of granulocyte and macrophage colonies.|
|Next Steps||Please study cytokine receptors.|