cAMP Transmits Messages Within the Cell
Many of the chemical messengers (eg, neurotransmitters, many hormones, and many mediators of inflammation) that transmit messages from one cell to another never enter the target cell. Instead, these so-called first messengers work by binding to a specific receptor on the cell surface. The receptor then stimulates or inhibits the production of a so-called second messenger within the cell. Because second messengers are small molecules, they can move signaling information quickly throughout the cytoplasm. The second messenger may then activate an effector within the cell, which then causes some alteration in the cell's metabolism or activities.
Many of the cell surface receptors are G-protein-coupled receptors, whose principal second messenger is cAMP. Typically, when a G-protein-coupled receptor binds to its particular ligand, the receptor either stimulates or inhibits the production of cAMP by the adenylyl cyclase associated with that receptor.16 The adenylyl cyclase can produce many molecules of cAMP, thus amplifying the signal.
cAMP Promotes Immune Homeostasis
Several lines of evidence have shown that cAMP serves as a second messenger in processes that help to maintain immune homeostasis in the skin. Drugs that are known to elevate intracellular cAMP levels tend to reduce the production of proinflammatory mediators and increase the production of anti-inflammatory mediators by cultured human keratinocytes, monocytes, and dendritic cells.17, 18, 19, 20 Several studies have also suggested that PKA is the downstream effector of cAMP in processes involved in immune homeostasis in the skin.21, 22, 23
PDE4 Promotes Inflammation
PDE4 is the predominant cAMP-degrading enzyme in various inflammatory cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.1 Proinflammatory mediators released by these cells lead to activation of and tissue infiltration by other immune cells, activation and hyperproliferation of keratinocytes, and development of psoriatic lesions.2 PDE4 promotes the production of proinflammatory mediators such as TNF-α, IL-17, and IFN-γ.11, 12, 13
Within immune cells, cAMP regulates pro- and anti-inflammatory mediators. cAMP has been shown to enhance and suppress various cytokines, chemokines, and leukotrienes, including:
|cAMP Enhances the Production of:||cAMP Suppresses the Expression of:|
|Anti-inflammatory cytokine IL-106||Proinflammatory cytokines (TNF-α and IL-12)24, 25|
|Proinflammatory chemokines (eg, macrophage inflammatory protein [MIP]-1α and -1β26)|
|Proinflammatory lipid mediator leukotriene B427|
PDE4 exclusively hydrolyzes cAMP. PDE4 is clearly of physiological importance because "chemical knockout" of PDE4 activity in animals produces potent anti-inflammatory actions.28 A seminal feature of PDE4 is its ability to target specific intracellular sites, whereby PDE4 may form part of spatially constrained signaling modules that generate and monitor cAMP gradients in cells and integrate actions with other signaling systems.28 Selective expression of both PDE4 and respective anchor proteins results in the regulation of cAMP signaling in a cell-type-specific fashion.28Discover the central role of PDE4 in regulating inflammation »
cAMP Regulates T Cell Function at the Level of Transcription Factors
T cells are effector cells that carry out various functions in an immune response. cAMP is well established as a potent negative regulator of T cell immune function. Through the PKA pathway, cAMP regulates T cell function at the level of transcription factors.
A 2011 review of nearly 200 studies found that the second messenger cAMP regulates T cell function in several ways, including at the level of transcription factors.29 T cells are a subset of lymphocytes, defined by their development in the thymus. They are effector cells that carry out various functions in an immune response: some activate macrophages, some help B cells to produce antibodies, and some kill cells infected with intracellular pathogens.30
Induction of cAMP levels in responder T cells has emerged as one of the mechanisms by which regulatory T (TR) cells execute their suppressive action.29 This regulation is a result of the cAMP and protein kinase A (PKA) pathway.29 In this molecular pathway, cAMP is the major second messenger responsible for intracellular signal transduction by means of G-protein coupled receptors, such as histamine, β-adrenergic, and prostaglandin receptors.29
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See PDE4’s Role in Autoimmune Disease
An activator of phosphorylase kinase and an effector of other enzymes, formed in muscle from ATP by adenylate cyclase and broken down to 5'‑AMP by a phosphodiesterase; the first known second messenger, it is a regulator of metabolism. A related compound (2',3') is also known.
One of the 2 major types of lymphocytes. B cells express but do not release surface immunoglobulins. B cells are the precursors of plasma cells, which are active in the formation and secretion of antibodies.
The smallest unit of living structure capable of independent existence, composed of a membrane‑enclosed mass of protoplasm containing a nucleus or nucleoid.
The general term for histologically apparent cytologic changes, cellular infiltration, and mediator release that occurs in affected blood vessels and adjacent tissue in response to injury or abnormal stimulation. The so‑called cardinal signs of rubor (redness), calor (heat), tumor (swelling), and dolor (pain) may or may not be present.
Cytokines produced by T cells, fibroblasts, and other cells in response to viral infection and other biologic and synthetic stimuli; IFNs bind to specific receptors on cell membranes.
Any of a group of multifunctional cytokines synthesized by lymphocytes, monocytes, macrophages, and lymphoid and nonlymphoid cells.
a member of the chemokine family that is chemotactic for certain lymphocyte subsets such as T‑cytotoxic cells.
A key enzyme involved in the cytokine production of inflammatory cells. PDE4 is an intracellular enzyme that promotes inflammation by degrading intracellular levels of cyclic adenosine monophosphate (cAMP), a naturally occurring second messenger that helps maintain immune homeostasis by modulating the production of pro‑ and anti‑inflammatory mediators.
A group of enzymes that are dependent on cyclic AMP and catalyze the phosphorylation of serine or threonine residues on proteins. Included under this category are two cyclic‑AMP‑dependent protein kinase subtypes, each of which is defined by its subunit composition.
Transfer of genetic code information from one kind of nucleic acid to another, especially with reference to the process by which a base sequence of messenger RNA is synthesized on a template of complementary DNA.
Any of several cytokines that function as cell‑associated or secreted proteins interacting with receptors of the tumor necrosis factor receptor (TNFR) family.
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