Cytokines
By Levi Clancy for Student Reader on
updated
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.
| Cytokine | Produced By | Immunity | Overview |
|---|---|---|---|
| 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 | Macrophages Fibroblasts | 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. |
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