Inside the Cell: An Overview of Intracellular Mechanisms of Inflammation

Inflammation and Immune Homeostasis

Inflammation is generally viewed as part of the body's normal response to injury or infection. However, an inflammatory response that is inappropriate (e.g. in response to self‑antigens), disproportionately severe, or inappropriately prolonged may become a problem in itself. Inflammatory responses are generally considered to be tightly regulated. Several regulatory mechanisms help to terminate responses to foreign antigens (to return the immune system to a basal state after the foreign antigen has been cleared) and to maintain unresponsiveness, or tolerance, to self‑antigens. Thus, these regulatory mechanisms help to establish immune homeostasis.9

If these homeostatic mechanisms fail, activated immune cells may continue to proliferate, to release proinflammatory mediators, and to recruit more immune cells to the affected site, thus creating a chronic cycle of aberrant inflammation.9

Much has been learned about the role of the extracellular microenvironment and extracellular proinflammatory mediators such as tumor necrosis factor (TNF)‑α, interleukin (IL)‑17, and interferon (IFN)‑γ in promoting aberrant inflammation.40

Key Immune Cells and Mediators in Psoriasis

Intracellular Inflammatory Pathways: Research in Immune‑Mediated Inflammatory Disease

There is also considerable interest in the role that intracellular signaling pathways could play in inflammation and immune homeostasis. These pathways involve various second messengers and effectors, including cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), Janus kinase (JAK), signal transducer and activator of transcription (STAT), mitogen‑associated protein kinase (MAPK), nuclear factor of kappa light polypeptide gene enhancer in B cells (NF‑κB), phosphatidylinositol 3‑kinase (PI3K), and spleen tyrosine kinase (Syk).10, 16, 69, 70, 71, 72

The cAMP/PKA Pathway Is an Intracellular Signaling System

Many of the receptors on the surface of a cell belong to a class called G‑protein–coupled receptors (GPCRs). The various members of this class of receptors can respond to a wide range of signals from the outside of the cell. GPCRs convey these signals to the inside of the cell, thus eliciting a series of reactions involving other proteins, nucleotides, and metal ions, which eventually deliver a message that may lead to an appropriate cellular and physiological response.73 When some GPCRs are activated (eg, by binding to their specific ligand), they can elicit the production of cAMP.16 cAMP then diffuses through the cytoplasm until it reaches its target protein, usually PKA.10, 74

Thus, cAMP serves as a second messenger within the cell, transmitting a signal from the cell surface to a target within the cell. The amplitude and duration of this signal is regulated by the members of a large and diverse class of enzymes called cyclic nucleotide phosphodiesterases (PDEs), some of which degrade cAMP to AMP.10

Video Place Holder Image

This animation provides a simplified overview of how degradation of cyclic adenosine monophosphate (cAMP) by PDE4 modulates the production of pro- and anti‑inflammatory mediators.1, 6, 75

PDE4 Promotes Inflammation by Degrading cAMP Within Immune Cells

Cyclic adenosine monophosphate (cAMP) is an endogenous second messenger that plays a key role in the regulation of many biologic responses in humans, including inflammation, apoptosis, and lipid metabolism. Cyclic AMP is believed to help maintain immune homeostasis by suppressing the release of proinflammatory mediators (eg, TNF‑α, IL‑17, IFN‑γ)1 and promoting the release of anti‑inflammatory mediators (eg, IL‑106) by immune cells. Also, numerous in vitro studies have shown that cAMP helps to regulate T cell function.29

Phosphodiesterase 4 (PDE4) is the predominant cAMP‑degrading enzyme expressed in inflammatory cells.1 Thus, PDE4 degradation of cAMP may promote immune cell activation and the release of proinflammatory mediators such as TNF‑α, IL‑17, and IFN‑γ.11, 12, 13 By breaking down cAMP, PDE4 indirectly decreases the production of anti‑inflammatory mediators such as IL‑10.6 PDE4 might therefore play a role in various inflammatory diseases, including psoriasis, psoriatic arthritis, and ankylosing spondylitis.

Role of Intracellular PDE4 in Psoriatic Arthritis and Psoriasis

PDE4 Potentiates Proinflammatory Response and Is Shown to Be Within Psoriatic Inflammatory Cells1

Psoriatic disease is associated with aberrant inflammation and the imbalance or overproduction of proinflammatory mediators. Current research regarding the immunopathogenesis of psoriasis supports the theory of a dysregulated immune system governed by proinflammatory cytokines, including TNF‑α, IL‑17, IL‑23, and other cytokines.40

Increased levels of proinflammatory mediators are found in the skin lesions and synovium of patients with psoriatic disease.40, 41 Evidence suggests that PDE4 plays a role in breaking down cAMP in immune cells. Thus, PDE4 is thought to be part of the system that regulates the release of these proinflammatory mediators.5

PDE4 in Psoriatic Arthritis (PsA)

Evidence suggests that PDE4 plays a role in the regulation of inflammatory mediators that are involved in psoriatic arthritis. Ex vivo studies have shown that the synovial tissue from persons with PsA produces abnormally large amounts of the proinflammatory cytokines that are associated with activated monocytes.44

Abnormal levels of pro‑ and anti‑inflammatory mediators in joint‑resident cells in the synovium could explain the characteristic swelling and tenderness of psoriatic arthritis.41

PDE4 in Psoriasis (PsO)

Research suggests that chronic plaque psoriasis represents an unresolved inflammation and proliferation of keratinocytes in the epidermis.31 Thus, it could represent a failure of immune homeostasis.9

Psoriatic plaques are circumscribed, discrete or confluent, reddish, silvery‑scaled macropapules that result from abnormal inflammation and proliferation of keratinocytes in the skin.31 PDE4, which has been shown to be present in inflammatory cells and is thought to be important to processes relevant to psoriasis, could play a role in promoting a proinflammatory intracellular response that leads to the formation of psoriatic skin lesions.1, 31

Exposing the Intracellular Relationship of PDE4 and cAMP in Inflammation

Exposing the Intracellular Relationship of PDE4 and cAMP in Inflammation

In vitro studies show that intracellular cAMP is degraded by cyclic nucleotide phosphodiesterase enzymes.10 These studies show that phosphodiesterase 4 (PDE4) is the predominant cAMP‑degrading enzyme in many inflammatory cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.1

Nonclinical studies have shown that by degrading cAMP, PDE4 predisposes the cell toward adopting an inflammatory state, thus leading to the production of proinflammatory mediators (eg, TNF‑α, IL‑17, and IFN‑γ)1 and decreasing production of anti‑inflammatory mediators (eg IL‑10).6

PDE4 Promotes the Release of Proinflammatory Mediators

PDE4 Promotes the Release of Proinflammatory Mediators

Because of its role in breaking down cAMP in immune cells, PDE4 is thought to be involved in promoting inflammation.1

PDE4 in Psoriatic disease

Psoriatic Disease

Psoriasis and psoriatic arthritis are inflammatory diseases with shared immunologic mechanisms.2 It is believed that once an immune cell has been activated, it releases proinflammatory mediators that can then activate other cells and promote proliferation, recruiting more cells to the site of disease.

The immune system has homeostatic mechanisms that help to regulate these inflammatory responses, to resolve inflammation after a foreign antigen has been cleared and to prevent the immune system from reacting to self‑antigens. Thus, chronic inflammation, such as in psoriasis, could result from some failure of immune homeostasis.9

PDE4 in psoriatic arthritis

Psoriatic Arthritis

Abnormal levels of pro‑ and anti‑inflammatory mediators in joint‑resident cells in the synovium may contribute to the characteristic swelling and tenderness of psoriatic arthritis.40, 41 Research into the role of the various pro‑ and anti‑inflammatory mediators in synovial fluid of patients with psoriatic arthritis is ongoing.

PDE4 in Psoriasis

Psoriasis

When inflammatory dysregulation activates keratinocytes in the skin, the keratinocytes proliferate and the skin becomes inflamed; this process may lead to the formation of psoriatic plaques.31 PDE4 is an intracellular enzyme that in preclinical models promotes production of proinflammatory mediators and decreases production of anti‑inflammatory mediators.1, 6

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Glossary:

Cyclic adenosine monophosphate (cAMP)

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.

Adenosine monophosphate (AMP), or adenylic acid

A condensation product of adenosine and phosphoric acid; a nucleotide found among the hydrolysis products of all nucleic acids. 3'‑Adenylic acid (adenosine 3'‑monophosphate) and 5'‑adenylic acid [adenosine 5'‑monophosphate (AMP)] differ in the place of attachment of the phosphoric acid to the D‑ribose; deoxyadenylic acid differs in having H instead of OH at the 2' position of D‑ribose.

B cells (or B lymphocyte)

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.

Cell

The smallest unit of living structure capable of independent existence, composed of a membrane‑enclosed mass of protoplasm containing a nucleus or nucleoid.

Phosphatidylinositol 3‑kinase (PI3K)

A phosphatidylinositol 3‑kinase subclass that includes enzymes formed through the heterodimerization of a p110 catalytic and a p85, p55, or p50 regulatory subunit. This subclass of enzymes is a downstream target of tyrosine kinase receptors and G‑protein‑coupled receptors.

Inflammation (or inflammatory response)

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.

Inflammatory

Pertaining to, characterized by, causing, resulting from, or becoming affected by inflammation.

Interferons (IFN)

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.

Interleukin (IL)

Any of a group of multifunctional cytokines synthesized by lymphocytes, monocytes, macrophages, and lymphoid and nonlymphoid cells.

Interleukin‑10 (IL‑10)

A cytokine derived from helper T cell lymphocytes (Th2) that inhibits mononuclear cell inflammation.

Intracellular

Within a cell or cells.

Janus kinase (JAK)

A family of nonspecific protein‑tyrosine kinases activated by binding of cytokines to their plasma membrane receptors; the kinases, bound to the cytoplasmic domains of the receptors, serve as intermediates linking the receptors to activation of the STAT family of transcription factors, which migrate to the nucleus to regulate gene expression.

Mitogen‑associated protein kinase (MAPK)

Any of several cytoplasmic protein kinases that make up the MAPK signaling cascade.

Phosphodiesterase (PDE)

Enzymes that cleave bonds in phosphodiesters, such as those in cAMP.

Phosphodiesterase 4 (PDE4)

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.

Psoriasis

A common dermatologic condition characterized by the eruption of circumscribed, discrete and confluent, reddish, silvery‑scaled maculopapules; the lesions occur predominantly on the elbows, knees, scalp, and trunk, and microscopically show characteristic parakeratosis and elongation of rete ridges with shortening of epidermal keratinocyte transit time due to decreased cyclic guanosine monophosphate

Protein kinase A (PKA)

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.

Psoriatic Arthritis

A form of polyarthritis (ie, affecting more than one joint) that occurs in patients with psoriasis; the arthritis resembles rheumatoid arthritis but is seronegative for rheumatoid factor and often involves the digits.

Signal transducer and activator of transcription (STAT)

A family of transcription factors containing SH2 domains that are involved in cytokine‑mediated signal transduction. STAT transcription factors are recruited to the cytoplasmic region of cell surface receptors and are activated via phosphorylation. Once activated, they dimerize and translocate into the cell nucleus, where they influence gene expression. They play a role in regulating cell growth processes and cell differentiation. STAT transcription factors are inhibited by suppressors of cytokine signaling proteins and protein inhibitors of activated STAT.

Spleen tyrosine kinase (Syk)

A non‑receptor tyrosine kinase critical for signaling B‑cell activation.

Tumor necrosis factor (TNF)

Any of several cytokines that function as cell‑associated or secreted proteins interacting with receptors of the tumor necrosis factor receptor (TNFR) family.

View All References »

References:

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See PDE4's Role in Autoimmune Disease

See PDE4's Role in Autoimmune Disease