Complex interactions among various cells of the immune response are mediated by a group of secreted low-molecular weight proteins that are collectively designated as cytokines. Cytokines are the messenger molecules of the immune system.
Generally, they act locally, not systemically.
General Properties:
Secreted by one cell type --act upon cells which bear a receptor for the cytokine. Very high affinity between the cytokine and its receptor which allows even very small quantities of cytokines to have a potent effect. When the cytokine binds to its receptor, it triggers intracellular signals (signal transduction pathways) which lead to specific changes in gene expression.
autocrine - binding to the same cell that secreted it
paracrine - binding to a nearby cell
endocrine - binding to a distant cell
Actions of cytokines may be:
-pleiotropic (they elicit different biological activities from different target cells.
-redundant - different cytokines can mediate similar functions.
-synergy - the combined effect on cellular activity of two cytokines may be greater than the additive effects of the individual cytokines.
-antagonism - the effects of one cytokine may inhibit the effects of another cytokine.
These attributes allow cytokines to regulate cellular activity in a coordinated, interactive manner.
Example: Cytokines secreted by a single lymphocyte following antigen-specific activation can influence the activity of various cells involved in the immune response. For example, cytokines produced by activated Th cells can influence the activity of B cells, Tc cells, NK cells, macrophages, granulocytes, and hematopoietic stem cells, thereby activating an entire network of interacting cells.
Specificity of cytokine action is maintained by the careful regulation of the expression of cytokine receptors. Often cytokine receptors are expressed only after an encounter with antigen.
Cytokines generally are secreted following activation of a particular cell and secretion is short-lived, generally ranging from a few hours to a few days.
Another mechanism providing for specificity is the frequent requirement for cell -to-cell contact to generate effective concentrations of a cytokine at the juncture of interacting cells.
It wasn't until cytokines were purified and cytokine genes eventually cloned that the vast array of factors generated in different biological systems could be shown to represent the activities of a "fairly" limited number of cytokines.
Most of the cytokines have been designated as INTERLEUKINS in reference to their role in cellular communication among leucocytes. Interleukin1 and Interleukin 2 were discovered first and are very well characterized. To date, we are up to (at last count) IL-18.
Some cytokines are known by common names. For instance, there are the interferons, the tumor necrosis factors, and the transforming growth factors. In addition, a group of low-mw cytokines, including interleukin 8, are classified in the chemokine family. These molecules (the chemokines) play an important role in inflammation, and recently, certain chemokine receptors have been found to serve as co-receptors for the HIV virus.
CYTOKINES PRODUCED PRIMARILY BY MACROPHAGES
Interleukin 1 (IL-1)
Two forms: IL-1 alpha (membrane form) and IL-1 beta (secreted form)
-IL-1 is secreted by activated antigen presenting cells [B cells and dendritic cells in addition to macrophages]
Target Cells:
Very pleiotropic
Th cells ---co-stimulates activation
B cells----Promotes maturation and clonal expansion
NK cells---- Enhances activity
Vascular Endothelial Cells---increases expression of ICAMs
Macrophages and neutrophils-----chemotactically attracts
If IL-1 is administered in vivo, neutrophils and macrophages are induced to leave the bone marrow, enter the circulation, and then extravasate through the capillary walls into tissue spaces. Both neutrophils and macrophages are chemotactically attracted to IL-1, facilitating the build-up of phagocytic cells during an inflammatory reaction.
Hepatocytes---induces synthesis of acute phase proteins
Hypothalamus---induces fever, somnolence, anorexia.
IL-1 is ~17kDa in mw.
The two forms of IL-1 differ in charge, and can be separated by IEF.
Two independent genes (IL-1 alpha and IL-1 beta) encode the two IL-1 polypeptides. The two genes have 27% sequence homology. Both bind to the same receptor.
IL-1alpha also exists in membrane-associated form (mIL-1) which may serve to activate T cells following membrane interaction.
A Major function of IL-1 is the activation of Th cells (Th2 cells)
A specific signal is generated by the interaction of T cell Receptors with processed antigen + Class II MHC. Even with the co-stimulatory signal of B7 - CD28 interaction binding of either soluble IL-1 or MIL-1 is usually also required.
IL-1 also is now known to be synthesized by snails, echinoderms, tunicates, etc.
IL-6
Has many properties in common with IL-1 [works as more-or-less a cofactor]
Secreted by:
monocytes, macrophages, bone-marrow stromal cells, Th2 cells.
Target Cells:
Proliferating B Cells----Promotes terminal differentiation into plasma cells.
Plasma Cells----Stimulates antibody secretion
Myeloid Stem Cells------- Helps promote differentiation
Hepatocytes----Induces the synthesis of acute-phase proteins
IL-12
IL-12 is produced by activated antigen presenting cells [B cells and Macrophages] and acts on Th1 cells, NK cells, and Tc cells.
IL-12 has been shown to promote the differentiation of Th1 cells from the Th0 stage.
It also is a costimulator of Th1 activity (causes these cells to secrete IL-2 and IFN-gamma and express IL-2R).
In addition, IL-12 acts synergistically with IL-2 to induce CTLs.
IL-12 also enhances NK cell and Th1 cell proliferation.
Tumor Necrosis Factor alpha
produced by: macrophages and by mast cells
Has a cytotoxic effect on tumor cells but also acts as an inflammatory mediator. It induces cytokine secretion and is responsible for cachexia associated with chronic inflammation.
Functions:
causes increased IL-1 and IL-6 by macrophages
production of TNF alpha is triggered by LPS, bacterial toxins, viruses, tumor cells, parasites, etc.
activation of B & T lymphocyte proliferation
causes the plethora of symptoms of gram - septic shock including: fever, rigors, muscle pain, and hyoptension.
the wasting (cachexia) observed in AIDS and Cancer is due to TNF alpha
TNF alpha also kills some tumor cell lines
Previous
| Next
| 328 Syllabus
| Biology Home
| WKU Home
| Research Paper Topics
Lecture 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29