a. Tumor necrosis factor-alpha (TNF-α)
TNF-α is the principle cytokine that mediates acute inflammation. In excessive amounts it also is the principal cause of systemic complications such as the shock cascade. Functions include acting on endothelial cells (def) to stimulate inflammation (def) and the coagulation pathway; stimulating endothelial cells to produce selectins and ligands for leukocyte integrins during diapedesis (def); stimulating endothelial cells and macrophages to produce chemokines (def) that contribute to diapedesis, chemotaxis (def), and the recruitment of leukocytes; stimulating macrophages to secrete interleukin-1 (IL-1) for redundancy; activating neutrophils (def) and promoting extracellular killing by neutrophils; stimulating the liver to produce acute phase proteins (def), and acting on muscles and fat to stimulate catabolism for energy conversion. TNF-α stimulates the endothelial cells that form capillaries to express proteins that activate blood clot formation within the capillaries. This occludes local blood flow to help prevent microbes from entering the bloodstream. In addition, TNF is cytotoxic for some tumor cells; interacts with the hypothalamus to induce fever and sleep; stimulates the synthesis of collagen and collagenase for scar tissue formation; and activates macrophages. TNF is produced by monocytes,macrophages, dendritic cells, TH1 cells, and other cells.
b. Interleukin-1 (IL-1)
IL-1 function similarly to TNF in that it mediates acute inflammatory responses. It also works synergistically with TNF to enhance inflammation. Functions of IL-1 include promoting inflammation (def); activating the coagulation pathway, stimulating the liver to produce acute phase proteins (def), catabolism of fat for energy conversion, inducing fever and sleep; stimulates the synthesis of collagen and collagenase for scar tissue formation; stimulates the synthesis of adhesion factors on endothelial cells and leukocytes (see Fig. 1) for diapedesis (def); and activates macrophages. IL-1 is produced primarily by monocytes, macrophages, dendritic cells, endothelial cells, and some epithelial cell.
c. Chemokines (def)
Chemokines are a group of cytokines that enable the migration of leukocytes from the blood to the tissues at the site of inflammation. They increase the affinity of integrins on leukocytes for ligands on the vascular wall (see Fig. 1 during diapedesis (def), regulate the polymerization and depolymerization of actin in leukocytes for movement and migration, and function as chemoattractants (def) for leukocytes. In addition, they trigger some WBCs to release their killing agents for extracellular killing and induce some WBCs to ingest the remains of damaged tissue. Certain chemokines promote angiogenesis (def). Chemokines also regulate the movement of B-lymphocytes (def), T-lymphocytes (def), and dendritic cells (def) through the lymph nodes and the spleen. When produced in excess amounts, chemokines can lead to damage of healthy tissue as seen in such disorders as rheumatoid arthritis, pneumonia, asthma, adult respiratory distress syndrome (ARDS), and septic shock. Examples of chemokines include IL-8, MIP-1a, MIP-1b, MCP-1, MCP-2, MCP-3, GRO-a, GRO-b, GRO-g, RANTES, and eotaxin. Chemokines are produced by many cells including leukocytes, endothelial cells, epithelial cells, and fibroblasts.
d. Interleukin-12 (IL-12)
IL-12 is a primary mediator of early innate immune responses to intracellular microbes. It is also an inducer of cell-mediated immunity. It functions to stimulate the synthesis of interferon-gamma by T-lymphocytes (def) and NK cells (def); increases the killing activity of cytotoxic T-lymphocytes (def) and NK cells; and stimulates the differentiation of naive T4-lymphocytes (def) into interferon-gamma producing TH1 cells. It is produced mainly by macrophages and dendritic cells.
e. Type I Interferons (def)
Interferons modulate the activity of virtually every component of the immune system. Type I interferons include 13 subtypes of interferon-alpha, interferon-beta, interferon omega, interferon-kappa, and interferon tau. (There is only one type II interferon, interferon-gamma, which is involved in the inflammatory response.)
The most powerful stimulus for type I interferons is the binding of viral DNA or RNA to toll-like receptors (def) TLR-3, TLR-7, and TLR-9 in endosomal membranes (def).
a. TLR-3 - binds double-stranded viral RNA;
b. TLR-7 - binds single-stranded viral RNA, such as in HIV, rich in guanine/uracil nucleotide pairs;
c. TLR-9 - binds unmethylated cytosine-guanine dinucleotide sequences (CpG DNA) found in bacterial and viral genomes but uncommon or masked in human DNA and RNA.
by Gary E. Kaiser, Ph.D.
Professor of Microbiology, The Community College of Baltimore County, Catonsville Campus
This work is licensed under a Creative Commons Attribution 4.0 International License.
Based on a work The Grapes of Staph at https://cwoer.ccbcmd.edu/science/microbiology/index_gos.html.Last updated: August, 2019
Please send comments and inquiries to Dr. Gary Kaiser
Signaling pattern recognition receptors located in the cytoplasm of cells such as RIG-1 and MDA-5 also signal synthesis and secretion of type-I interferons.
Type I interferons, produced abundantly by plasmacytoid dendritic cells, by virtually any virus-infected cell, and by other defense cells provide an early innate immune response against viruses. Interferons induce uninfected cells to produce an enzyme capable of degrading viral mRNA, as well as one that blocks translation in eukaryotic cells. These enzymes remain inactive until the uninfected cell becomes infected with a virus. At this point, the enzymes are activated and begin to degrade viral mRNA and block translation in the host cell. This not only blocks viral protein synthesis, it also eventually kills the infected cell (see Fig. 2A and Fig. 2B). In addition, type I interferons also cause infected cells to produce enzymes that interfere with transcription of viral RNA or DNA. They also promote body defenses by enhancing the activities of CTLs, macrophages, dendritic cells, NK cells, and antibody-producing cells, as well as induce chemokine production to attract leukocytes to the area.
| by Gary E. Kaiser, Ph.D. Last updated: August, 2019 |
Type I interferons also induce MHC-I antigen expression needed for recognition of antigens by cytotoxic T-lymphocytes (def); augment macrophages (def), NK cells (def), cytotoxic T-lymphocytes, and B-lymphocytes (def) activity; and induce fever. Interferon-alpha is produced by T-lymphocytes (def), B-lymphocytes, NK cells, monocytes/macrophages; interferon-beta by virus-infected cells, fibroblasts, macrophages, epithelial cells, and endothelial cells.
f. Interleukin-6 (IL-6)
IL-6 functions to stimulate the liver to produce acute phase proteins (def); stimulates the proliferation of B-lymphocytes (def); and increases neutrophil (def) production. IL-6 is produced by many cells including T-lymphocytes, macrophages, monocytes, endothelial cells, and fibroblasts.
g. Interleukin-10 (IL-10)
IL-10 is an inhibitor of activated macrophages and dendritic cells and as such, regulates innate immunity and cell-mediated immunity. IL-10 inhibits their production of IL-12, co-stimulator molecules, and MHC-II molecules (def), all of which are needed for cell-mediated immunity (def). IL-10 is produced mainly by macrophages, and TH2 cells.
h. Interleukin 15 (IL-15)
IL-15 stimulates NK cell (def) proliferation and proliferation of memory T8-lymphocytes (def). IL-15 is produced by various cells including macrophages.
i. Interleukin-18 (IL-18)
IL-18 stimulates the production of interferon-gamma by NK cells (def) and T-lymphocytes (def) and thus induces cell-mediated immunity (def). It is produced mainly by macrophages.