The Cytokines (def)
Cytokines are a group of intercellular regulatory proteins that ultimately control every aspect of body defense and are produced by many different cells in the body. Cytokines activate and deactivate phagocytes and immune defense cells, increase or decrease the functions of the different immune defense cells, and promote or inhibit a variety of innate body defenses. The same cytokine often carries out multiple functions that overlap with those of other cytokines and cytokines often interact in complex ways with one another.
Proinflammatory cytokines, such as Interleukin-1 (Il-1), interleukin-6 (Il-6), and tumor necrosis-alpha (TNF-alpha), promote the inflammatory response and result in the synthesis of acute phase proteins. Other cytokines, such as interleukins - 4, -5, -10, and -14 (Il-4, Il-5, Il-10, Il-14) promote antibody responses. Still other cytokines, such as interleukin-2 (Il-2) and interferon-gamma (IFN-gamma) promote cell-mediated immunity.
We will now look at several of the cytokines mentioned throughout this course and some of their major effects.
a. Interleukin-1 (IL-1)
Activates resting T4-lymphocytes, B-lymphocytes, NK cells, polymorphonuclear leukocytes, endothelial cells, smooth muscle cells, and fibroblasts; induces fever, sleep, anorexia and neutrophilia; stimulates synthesis of proinflammatory cytokines and acute-phase proteins; induces coagulation; stimulates the synthesis of collagen and collagenase for scar tissue formation; stimulates the synthesis of adhesion factors on endothelial cells and leukocytes for diapedesis; activates macrophages; promotes inflammation, and catabolic processes. Produced by monocytes, macrophages, dendritic cells, and a variety of other cells in the body.
b. Interleukin-2 (IL-2)
A growth and differentiation factor for activated T4-lymphocytes, T8-lymphocytes, B-lymphocytes, and NK cells; promotes antibody secretion by B-lymphocytes; induces the synthesis of other cytokines such as interferon-gamma and TNF-beta; activates cytotoxic T-lymphocytes, NK cells, and monocytes/macrophages. Produced primarily by activated T4-lymphocytes.
c. Interleukin-3 (IL-3)
Supports the growth of multilineage bone marrow stem cells; a growth factor for mast cells. Produced by activated T-lymphocytes, NK cells, and other cells.
d. Interleukin-4 (IL-4)
A growth and differentiation factor for activated B-lymphocytes and activated T-lymphocytes; promotes production of TH2 cells and IgE by B-lymphocytes; enhances macrophage antigen processing and presentation activity; induces other cytokine production; induces immunoglobulin class shift in B-lymphocytes a growth factor for mast cells. Produced by TH2 cells as well as other cells.
e. Interleukin-5 (IL-5)
Stimulates the proliferation of activated B-lymphocytes and their differentiation into plasma cells; stimulates antibody secretion and immunoglobulin class shift; induces growth and differentiation of eosinophils. Produced primarily by TH2 cells.
f. Interleukin-6 (IL-6)
Functions similarly to interleukin-1 for redundancy in biological activities. Produced by many cells including T-lymphocytes, macrophages, and monocytes.
g. Interleukin-8 (IL-8)
A chemokine (def); chemotactic for neutrophils; activates and triggers extracellular killing by neutrophils; enhances adherance of phagocytes to endothelial cells and diapedesis. Produced by monocytes, macrophages, and other cells.
h. Interleukin-10 (IL-10)
A multifunctional cytokine that modulates the function of many immunocompetent cells, including T-lymphocytes, B-lymphocytes, NK cells, monocytes/macrophages, and neutrophils. Produced by T- and B-lymphocytes.
i. Interleukin-12 (IL-12)
Activates TH1 induction and maturation; activates interferon-gamma production; enhances the cytolytic activity of CTLs, NK cells, and macrophages. Produced primarily by monocytes/macrophages and dendritic cells.
j. Other Chemokines (def)
Chemokines are a group of cytokines that mobilize white blood cells (WBCs) to sites of inflammation. They pull the WBCs out of the bloodstream and chemotactically attract them to the inflammatory site, trigger some WBCs to release their killing agents for extracellular killing, and induce some WBCs to ingest the remains of damaged tissue. Certain chemokines have also been shown to suppress HIV, probably by binding to the chemokine receptors serving as the second binding factor for HIV on CD4+ cells. 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.
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.
k. Interferons (IFN)
Interferons modulate the activity of virtually every component of the immune system. Type I interferons include more than 20 types of interferon-alpha, interferon-beta, interferon omega, and interferon tau. There is only one type II interferon, interferon-gamma. Type I interferons, that can be produced by virtually any virus-infected cell is better able to induce viral resistance in cells, where as type II interferon is produced by activated T-lymphocytes as part of an immune response and functions mainly to promote the activity of the components of the cell-mediated immune system such as CTLs, macrophages, and NK cells.
1. interferon-gamma (IFN-gamma)
Induces MHC-I and MHC-II production; activates and increases the antimicrobial and tumoricidal activity of monocytes/macrophages, neutrophils, and NK cells; stimulates the synthesis of adhesion factors on endothelial cells and leukocytes for diapedesis; augments or inhibits other cytokine activities; inhibits TH2 cell production and activities; exerts weak antiviral activity. Produced primarily by TH1 cells and other cells.
2. interferon-alpha (IFN-alpha) and interferon-beta (IFN-beta)
Exerts antiviral and antiparasitic activity; induces MHC-I antigen expression; augments macrophage, NK cell, CTL, and B-lymphocyte activity; has fever-inducing and antiproliferative properties. Interferon-alpha is produced by T-lymphocytes, B-lymphocytes, NK cells, monocytes/macrophages; interferon-beta by virus-infected cells, fibroblasts, macrophages, epithelial cells, and endothelial cells.
Interferons are among the best studied cytokines. Produced by immune-activated cells or virus-infected cells in response to the double-stranded RNA (dsRNA) that many viruses produce as a part of their life cycle, interferons exert their antiviral activity by binding to uninfected neighboring cells and inducing them to produce enzymes that degrade mRNA. This not only prevents translation of viral mRNA into viral protein it also eventually kills the host cell, the factory producing the viruses. Interferons also promote body defenses by enhancing the activities of CTLs, macrophages, NK cells, and antibody-producing cells.
l. Tumor necrosis factors
1. tumor necrosis factor-alpha (TNF-alpha; cachectin)
TNF is a potent mediator of inflammatory and immune functions. It is cytotoxic for some tumor cells; induces fever and sleep; stimulates the synthesis of cytokines; stimulates the synthesis of collagen and collagenase for scar tissue formation; stimulates the synthesis of adhesion factors on endothelial cells and leukocytes for diapedesis; activates macrophages; promotes inflammation and catabolic processes; a chemoattractant for phagocytes and promotes neutrophil degranulation; responsible for endotoxin-induced septic shock; triggers apoptosis. Produced by monocytes/macrophages, TH1 cells, and other cells.
2. tumor necrosis factor-beta (TNF-beta; lymphotoxin)
Carries out many of the same activities as TNF-alpha. Produced primarily by TH1 cells and B-lymphocytes.
m. Colony-stimulating factors (CSF)
Promote the production of colonies of the different leukocytes in the bone marrow and enhance their activity. Examples include granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), and macrophage colony stimulating factor (M-CSF). In addition to their role in promoting production of leukocyte colonies, the CSFs also appear to promote their function. For example, when GM-CSF binds to receptors on neutrophils, eosinophils, and monocytes, it activates these cells and inhibits their apoptosis. GM-CSF increases adhesion of these cells to capillary walls during diapedesis, enhances their phagocytosis and extracellular killing, and increases both superoxide anion generation and antibody-dependent cytotoxicity. The various CSFs are produced by T-lymphocytes, monocytes/macrophages, and other cells.
The formation of granuloma (def) in infections such as tuberculosis, leprosy, histoplasmosis, and coccidioidomycosis is a cytokine-mediated cellular response. Because macrophages have difficulty in removing the microbes that cause these infections, there is a continuous secretion of cytokines and chemokines that leads to an accumulation of densely packed macrophages arond the microbes. The macrophages release fibrogenic cytokines such as TNF-alpha and IL-1 that lead to the formation of granulation tissue and scar tissue. The resulting mass is called a granuloma and is an attempt by the body to "wall-off" or localize the infection.