Frequently Asked Questions (FAQ): PDE4 and Psoriatic Arthritis

Psoriatic Arthritis

What is psoriatic arthritis (PsA)?

Psoriatic arthritis is a systemic inflammatory disorder characterized by stiffness, pain, swelling, and tenderness of the joints and the surrounding ligaments and tendons in patients with cutaneous psoriasis.57 One characteristic finding is enthesitis, which is inflammation of the enthesis, which is the anatomic location where tendons, ligaments, or joint capsule fibers are inserted into bone.57 In the fingers, the combination of joint inflammation and enthesitis can lead to dactylitis, or “sausage fingers.” Cases of PsA usually arise within 5 to 10 years after the diagnosis of cutaneous psoriasis.7

What causes psoriatic arthritis (PsA)?

The causes of psoriatic arthritis are under investigation and are not completely understood. Ex vivo studies have shown that synovial tissue from persons with psoriatic arthritis releases abnormally large amounts of the inflammatory cytokines associated with activated monocytes.44 These findings suggest a possible mechanism for the characteristic swelling and tenderness of PsA.

Nonclinical studies have shown that PDE4 plays an important role in the regulation of the pro‑ and anti‑inflammatory mediators that are involved in psoriatic arthritis.1 Thus, PDE4 could be involved in the pathophysiology (mechanism of disease) of psoriatic arthritis. Research into the role of the various pro‑ and anti‑inflammatory mediators in synovial fluid of patients with psoriatic arthritis is ongoing.

Where can I find more information about psoriatic arthritis?

PDE4/cAMP

What is PDE4?

Phosphodiesterase 4 (PDE4) is thought to be a key intracellular enzyme involved in regulating the production of inflammatory mediators by immune cells.1 PDE4 is a naturally occurring enzyme that degrades cyclic adenosine monophosphate (cAMP), a naturally occurring second messenger within cells. Nonclinical studies show that degradation of cAMP by PDE4 leads to immune cell activation and the release of pro‑inflammatory mediators such as TNF‑α, IL‑17, and IFN‑γ.1 In nonclinical models, the degradation of cAMP also decreases the production of anti‑inflammatory mediators such as IL‑10.6 Because of its ability to degrade cAMP, thus altering the immune cells’ production (balance) of pro‑ and anti‑inflammatory mediators, PDE4 could play a role in a number of inflammatory diseases, including psoriasis, psoriatic arthritis, and ankylosing spondylitis.

How is PDE4 involved in immune system disorders?

PDE4 is believed to promote production of pro‑inflammatory mediators by degrading cAMP to AMP. Nonclinical models show that degradation of cAMP by PDE4 results in immune cell activation and the release of pro‑inflammatory mediators such as TNF‑α, IL‑17, and IFN‑γ.1

Activated immune cells proliferate, release more proinflammatory mediators, and recruit more immune cells to the site of disease.2 If these responses are not properly regulated by homeostatic mechanisms, an imbalanced production of pro‑ and anti‑inflammatory mediators could result in inflammatory disease.

What role does PDE4 play in inflammation and inflammatory diseases?

Nonclinical studies show that the cAMP/PKA pathway plays an important regulatory role in several cell types involved in the pathophysiology of inflammatory diseases.1 Nonclinical studies also show that PDE4 degradation of cAMP may promote immune cell activation and the release of proinflammatory mediators such as TNF‑α, IL‑17, and IFN‑γ11, 12, 13. Other studies have shown that PDE4 indirectly downregulates the production of anti‑inflammatory mediators such as IL‑10.6

Because of its ability to degrade cAMP, thus altering the production of pro‑ and anti‑inflammatory mediators by immune cells, PDE4 may play a key role in a number of inflammatory diseases, including psoriasis, psoriatic arthritis, and ankylosing spondylitis.

What is cAMP and how is cAMP regulated by PDE4?

Cyclic adenosine monophosphate (cAMP) is a naturally occurring second messenger that plays a key role in the regulation of many biologic responses in humans, including inflammation. This regulation is a result of the cAMP and protein kinase A (PKA) pathway,a common and versatile signaling mechanism that is involved in the regulation of various cellular functions in eukaryotic cells.10

In immune cells, cAMP serves as a second messenger to help maintain immune homeostasis by modulating the proinflammatory and anti‑inflammatory mediators and T‑cell function.29 cAMP levels within immune cells are regulated by phosphodiesterase 4 (PDE4). PDE4 is the predominant cAMP‑degrading enzyme in many inflammatory cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.1

What is the relationship between cAMP/PDE4 and inflammatory disease?

Phosphodiesterase 4 (PDE4) is the predominant cAMP‑degrading enzyme in many inflammatory cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.1

Nonclinical studies show that the cAMP/PKA pathway plays an important regulatory role in several cell types involved in the pathophysiology of inflammatory diseases.1 Nonclinical models also show that by degrading cAMP, PDE4 predisposes immune cells toward adopting an inflammatory state, thus leading to the production of proinflammatory mediators (eg, TNF‑α, IL‑17, and IFN‑γ)11, 12, 13 and decreased production of anti‑inflammatory mediators (eg IL‑10).6

What intracellular inflammatory pathways are associated with PDE4?

The release of pro‑ and anti‑inflammatory mediators by immune cells is regulated in part by the cAMP/PKA pathway within the immune cells. The cAMP/PKA pathway is a common and versatile signaling mechanism in eukaryotic cells that is involved in the regulation of various cellular functions.10

Nonclinical studies have shown that the cAMP/PKA pathway is regulated by PDE4, which is the predominant cAMP‑degrading enzyme in immune cells. By degrading cAMP, PDE4 promotes the production of pro‑inflammatory mediators by immune cells.1

Nonclinical studies have shown that PDE4 degradation of cAMP leads to immune cell activation and the release of proinflammatory mediators such as TNF‑α, IL‑17, and IFN‑γ.1

Likewise, by breaking down cAMP, PDE4 indirectly decreases the production of anti‑inflammatory mediators such as IL‑10.6

How does PDE4 promote production of proinflammatory mediators?

PDE4 promotes production of proinflammatory mediators by degrading cAMP within immune cells. Degradation of cAMP by PDE4 leads to decreased activation of PKA and thus to immune cell activation and the release of proinflammatory mediators such as TNF‑α, IL‑17, and IFN‑γ.1

Likewise, by breaking down cAMP, PDE4 indirectly decreases the production of anti‑inflammatory mediators such as IL‑10.6

How does the PDE4 enzyme relate to tumor necrosis factor (TNF) and interleukins in psoriasis and psoriatic arthritis?

PDE4 is the predominant cAMP‑degrading enzyme in various inflammatory cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.1 By degrading cAMP, PDE4 predisposes the cell toward adopting an inflammatory state, thus leading to the production of proinflammatory mediators such as TNF‑α, IL‑17, and IFN‑γ.1

Release of inflammatory mediators like TNF‑α leads to activation of and tissue infiltration by other immune cells, thereby activating keratinocytes. When keratinocytes proliferate and the skin becomes inflamed, the result is the creation of psoriatic lesions or plaques.2 PDE4 potentiates this cycle of aberrant inflammation within key psoriatic inflammatory cells. Thus, PDE4 could be involved in the pathophysiology (mechanism of disease) of psoriasis and psoriatic arthritis.

In psoriatic arthritis, the production of proinflammatory mediators in joint‑resident cells of the synovium could lead to the characteristic swelling and tenderness.40, 41 In psoriasis, PDE4 is present in the relevant inflammatory cells1, 31 and is involved in several pathophysiological processes, including the production of TNF‑α, IL‑17, and IFN‑γ by monocytes/macrophages.1

What role does PDE4 play in the inflammatory processes involved in psoriasis and psoriatic arthritis?

Nonclinical studies have shown that PDE4 promotes production of proinflammatory mediators by converting cAMP to AMP in various inflammatory cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.1 Psoriatic disease is associated with aberrant inflammation and increased levels of pro‑inflammatory mediators.2

How is PDE4 involved in psoriatic arthritis (PsA)?

Proinflammatory mediators lead to infiltration of immune cells into the synovium.41 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 The presence of these proinflammatory mediators in synovial tissue and synovial fluid could provide a mechanism for the joint tenderness and swelling in cases of PsA.

In vitro studies have shown that agents that are known to activate the cAMP/PKA pathway in monocytes suppress their release of TNF‑α.33 PDE4 is the primary cAMP‑degrading enzyme in monocytes. The role of PDE4 in regulating the activity of the cAMP/PKA pathway could thus become important in PsA.

Cytokines

What are cytokines?

Cytokines can be broadly defined as cell‑signaling molecules that are secreted by cells for intercellular communication. Cytokines regulate many biological processes, including inflammatory and immune responses. Cytokines exert their effects by binding to a receptor on the surface of the target cell, thus activating a cascade of intracellular signals. Some chemokines bind to G‑protein‑coupled receptors, thus triggering adenylyl cyclase within the cell to produce cyclic adenosine monophosphate (cAMP). Once activated, adenylyl cyclase can produce many molecules of cAMP, thus amplifying the signal. The cAMP then diffuses through the cytoplasm to its effector, which is usually PKA.16 However, the signal can be limited or suppressed by cyclic nucleotide phosphodiesterase (PDE) enzymes.10 Some chemokines can activate the Janus kinase–signal transducer and activator of transcription (JAK‑STAT) pathway within the cell.69

What is the role of cytokines in psoriasis, psoriatic arthritis, and other inflammatory diseases?

Activated immune cells proliferate, release proinflammatory mediators (cytokines), and recruit more immune cells to the disease site, thus creating a chronic cycle of aberrant inflammation.31 This imbalanced production of pro‑ and anti‑inflammatory mediators can lead to psoriatic disease.2

Psoriatic disease is associated with aberrant inflammation and the production of proinflammatory mediators. Much has been learned about the roles of the extracellular microenvironment and proinflammatory mediators such as tumor necrosis factor (TNF)‑α, interleukin (IL)‑17, and interferon (IFN)‑γ in promoting aberrant inflammation.40 However, there is also considerable interest in how the various intracellular pathways, which involve various second messengers and effectors, including cAMP, PKA, JAK, MAPK, NF‑κB, PI3K, and Syk, could be involved in inflammatory processes.10, 69, 70, 71, 72

What cytokines are important in psoriasis (PsO)?

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 lesions and synovium of patients with psoriatic disease.40, 41

Molecular Targets

What are some of the molecular targets in psoriasis (PsO)?

Some of the molecular targets in PsO are on the outside of cells (eg, TNF‑α receptors).78 There is also considerable interest in the role that various intracellular signaling pathways could play in moderating inflammation. These pathways involve various second messengers and effectors, such as cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), Janus kinase (JAK), mitogen‑associated protein kinase (MAPK), nuclear factor of kappa light polypeptide gene enhancer in B cells (NF‑κB), phosphatidylinositol 3‑kinase (PI3K), spleen tyrosine kinase (Syk).10, 16, 69, 70, 71, 72

Cyclic adenosine monophosphate (cAMP) plays a key role in regulating the function of immune cells involved in psoriasis and psoriatic arthritis. This regulation is a result of the cAMP/PKA pathway, a common and versatile signaling mechanism involved in the regulation of various cellular functions.10 cAMP serves as a second messenger that helps to maintain immune homeostasis by modulating the production of proinflammatory and anti‑inflammatory mediators and T‑cell function at the level of transcription factors.29

Some chronic inflammatory diseases, possibly including plaque psoriasis, may represent a failure of immune homeostasis. In other words, an inflammatory response that has been set in motion does not resolve. Instead, a cycle of chronic inflammation is established.2

In vitro studies have shown that PDE4 is an intracellular enzyme that promotes production of proinflammatory mediators and decreases production of anti‑inflammatory mediators.1, 6 Thus, PDE4 could be involved in the pathophysiology (mechanism of disease) of psoriasis.

What molecular targets are being investigated in psoriatic arthritis (PsA)?

Cyclic adenosine monophosphate (cAMP) plays a key role in regulating the function of immune cells involved in psoriasis and psoriatic arthritis. This regulation is a result of the cAMP/PKA pathway, a common and versatile signaling mechanism involved in the regulation of various cellular functions.10 cAMP serves as a second messenger to help maintain immune homeostasis by modulating the proinflammatory and anti‑inflammatory mediators and T cell function.29

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 Studies have confirmed that increased levels of proinflammatory mediators are found in psoriatic lesions and the synovium of patients with PsA.40, 41

In vitro studies suggest that PDE4 is the predominant cAMP‑degrading enzyme in monocytes.1 Thus, PDE4 could play a role in the pathophysiology (mechanism of disease) of psoriatic arthritis. Dysregulation of the production of pro‑ and anti‑inflammatory mediators in joint‑resident cells in the synovium could account for the characteristic swelling and tenderness of PsA.44

Research is currently focused on understanding the broader inflammatory processes mediated by various intracellular pathways, including cAMP/PKA, JAK, MAPK, NF‑κB, and PI3K.10, 16, 69, 70, 71, 72

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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.

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.

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.

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.

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