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Inmunologia.org

Revisión
Vol. 22 / Núm 1/ Enero-Marzo 2003: 39-52 Phosphodiesterase Inhibitors as
Immunomodulatory Drugs
E. Layseca-Espinosa1, F. Sánchez-Madrid2, R. González-Amaro1 1Departamento de Inmunología, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., México, and 2Servicio de Inmunología, Hospital de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain. INHIBIDORES DE FOSFODIESTERASAS COMO FÁRMACOS INMUNOSUPRESORES
Los niveles intracelulares de nucleótidos cíclicos (cAMP, Intracellular levels of cyclic nucleotides (cAMP and cGMP) play a cGMP) tienen un papel esencial en la regulación de múltiples fun- critical role in many physiological processes of immune cells. Phosp- ciones de las células inmunes. Las fosfodiesterasas (FDEs) son un hodiesterases (PDEs) include a large group of related enzymes that have grupo grande de enzimas que ejercen un papel muy importante a pivotal role in the regulation of intracellular levels of cyclic nucleoti- en la regulación de los niveles intracelulares de nucleótidos cícli- des. Pentoxifylline (PTX) is a non-specific inhibitor of PDEs that shows cos. La pentoxifilina es un inhibidor no específico de FDE que many different effects on immune cells. The activation, cell prolifera- tiene diferentes efectos sobre células inmunitarias. Este fármaco tion, adhesion, polarisation and chemotaxis of T cells are down-regula- inhibe la activación, proliferación, adhesión, polarización y qui- ted in vitro by PTX. This drug also inhibits the synthesis of different miotaxis de linfocitos T. Además, la pentoxifilina bloquea la sín- pro-inflammatory cytokines, mainly tumour necrosis factor-α. Accor- tesis de diferentes citocinas pro-inflamatorias, principalmente del dingly, it has been found that PTX has a beneficial effect in vivo, in dif- factor de necrosis tumoral-α (TNF-α). En este sentido, se ha des- ferent immune-mediated and inflammatory conditions. On the other crito que este fármaco tiene un efecto benéfico en diferentes enfer- hand, rolipram is a potent PDE4-specific inhibitor that shows similar medades inflamatorias y mediadas inmunológicamente. Por otra immunomodulatory and anti-inflammatory properties. In addition, roli- parte, el rolipram es un potente inhibidor específico para la fami- pram has a down-regulatory effect on different phenomena involved in lia 4 de las FDE (PDE4) que muestra propiedades inmunomodu- immediate hypersensitivity reactions, including the synthesis of Th2 ladoras y antiinflamatorias similares a la pentoxifilina. Además, cytokines, IgE production and the activation of basophils and eosinop- rolipram ejerce un efecto inhibidor sobre diferentes fenómenos hils. PDE inhibitors are very interesting drugs with a great therapeu- involucrados en reacciones alérgicas o de hipersensibilidad inme- tic potential for the treatment of immune-mediated and inflammatory diata, incluyendo la síntesis de citocinas Th2, la producción de IgE y la activación de basófilos y eosinófilos. Los inhibidores deFDE son un grupo muy interesante de substancias que tienen un KEY WORDS: Pentoxifylline/ Rolipram/ T lymphocytes/ Cytokines/ gran potencial terapéutico para el tratamiento de enfermedades inflamatorias y mediadas inmunológicamente.
PALABRAS CLAVE: Pentoxifilina/ Rolipram/ Linfocitos T/ Cito-cinas/ Factor de necrosis tumoral-α.
PHOSPHODIESTERASE INHIBITORS AS IMMUNOMODULATORY DRUGS INTRODUCTION
by which PDEs are regulated: a) regulation by substrate Cyclic nucleotides (cAMP and cGMP) are intracellular availability; b) regulation by extracellular signals, and; c) second messengers that play a central role in signal feedback regulation. Another factor that can influence the transduction in many physiological processes(1). Intracellular activity of PDEs is their cellular compartmentalisation affected levels of these nucleotides are tightly regulated at the level by covalent modifications, such as prenylation, or by specific of synthesis by receptor-linked enzymes (such as adenylyl targeting sequences in the PDE primary structure, and and guanylyl cyclases) as well as by degradation by enzymes translocation of PDEs between compartments within a cell(13). known as phosphodiesterases (PDEs). These enzymes Since Sutherland and Rall, in the late 1950s, described catalyse the hydrolysis of the 3',5'-phosphodiester bond that the mechanism by which caffeine exerts its effects of adenosine 3',5'-monophosphate (cAMP) and guanosine involved the inhibition of cAMP PDE activity(14), a great 3',5'-monophosphate (cGMP), resulting in the formation of number of PDE inhibitors have been synthesised, such as the 5'-nucleotide metabolites (AMP and GMP). the widely used 3-isobutyl-1-metylxanthine (IBMX). Many PDEs include a large group of structurally related of these compounds are non-selective and inhibit distinct enzymes. Currently, eleven PDE gene families have been PDE families. The design of family-specific PDE inhibitors, identified, which differ in their primary structures, affinity such as the PDE4 inhibitor rolipram, has significantly for cAMP and cGMP, response to effectors, sensitivity to contributed to the advance in PDE research.
specific inhibitors, and mechanism of regulation(2-6). Within The immunoregulatory properties of cyclic adenosine the different families, tissue-specific mRNAs are generated monophosphate (cAMP) were first reported by Lichtenstein by alternative splicing. More than 50 mRNA splicing isoforms and cols., who described the effect of cAMP in the cytolytic have been detected in various human tissues, and these activity of lymphocytes, and in the IgE-mediated release of isoforms are differentially expressed and regulated in distinct histamine(1,15-17). Modulation of immune cell function by cell types and subcellular compartments(7). selective PDE inhibitors is limited to some specific PDE PDEs share a common structure. Each PDE has a conserved types. Although immune cells express several families of catalytic domain of ~250 amino acids, with a high degree PDEs (e.g., PDE4, PDE3, and, to a lesser extent, PDE7), PDE4 of conservation (25-40%) of amino acid sequence among seems to be the major contributor to cAMP hydrolysis in PDE families, which is located C-terminal to its regulatory these cells(2). In immune cells, elevation of intracellular domain. The catalytic core is proposed to contain common cAMP levels, mediated predominantly through inhibition structural elements important for the hydrolysis of the cyclic of PDE4, results in a wide range of anti-inflammatory and nucleotide phosphodiester bond as well as determinants responsible for differences in substrate affinity and inhibitorsensitivity among the different families(8). Rolipram, anefficient inhibitor of PDE4, is a competitive inhibitor(9) and PHARMACOLOGY OF PDE INHIBITORS
binds with a 1:1 stoichiometry within the catalytic domain Pentoxifylline (PTX) is a methylxantine derivative that of the enzyme(10). It is very likely that many of the known can be administered through oral or intravenous routes.
PDE inhibitors also bind to the active site of the enzyme.
This drug shows a rapid intestinal absorption, and peak The N- and C- termini display moderate homology plasma concentrations are obtained at 3.2 hours. Mean peak within the different PDE families and confer functional plasma levels of PTX after the administration of an oral fingerprints to the specific isoforms. The N-terminal half dose of 400 mg are 55 ± 22 ng/ml(18). In patients with hepatic of PDEs contain determinants that confer regulatory properties failure, raised levels of PTX have been reported (413 ± 445 specific to the different families(7,11), e.g., calmodulin-binding ng/ml), with no apparent toxicity(18). Absolute bioavailability domains (PDE1), membrane-targeting (PDE4) or hydrophobic of PTX time-release caplets is 20%. PTX is metabolised by membrane-association (PDE3) domains, two non-catalytic red blood cells and the liver, and has an elimination half- cyclic nucleotide binding domains (PDEs 2, 5 and 6), life of 3.4 hours. There is extensive entero-hepatic recycling calmodulin-, cAMP-, and cGMP-dependent protein kinase of metabolites. More than 90% of absorbed PTX is excreted phosphorylation sites (PDE1, 3, 4 and 5), etc. On the other in the urine in the form of six different metabolic products, hand, the C-termini regions possess docking sites for PDE- but an additional metabolite as well as PTX are not excreted specific kinases and have been involved in dimerisation(12).
by the kidney. It has been proposed that these metabolites Modulation of PDE function in cells is critical for the have more pronounced pharmacologic effects than the maintenance of cyclic nucleotide levels within a narrow primary drug(19). The more frequent side-effects of PTX are range of concentrations. There are three general mechanisms cutaneous reactions, nausea, vomiting, and diarrhoea.
TABLE I. Effects of Pentoxifylline
Function
Cell type
• ↓ Expression of CD25, CD69 and CD98• ↓ [Ca2+] intracellular• ↓ Activation of Na+/H+ antiporter• ↓ Cell cycle progression• ↓ Cell proliferation • ↓ Adhesion through β1 and β2 integrins• ↓ Activation of β1 integrins• ↓ Homotypic aggregation induced by β1 and β2 integrins• ↓ Polarisation• ↓ Chemotaxis• ↓ Transendothelial migration • ↓ Adhesion to fibronectin, HUVEC, and cultured • ↓ Polarization• ↓ Chemotaxis• ↓ Transendothelial migration • ↓ Ig Kappa light chain gene transcription • ↓ TNF-α, IL-6, IFN-γ, IL-2, IL-12, TNF-RII• ↑ IL-4, IL-10 • ↓ TNF-α, IL-6, IL-1β, IL-10, IL-12p35 • ↓ MIP-1α, MIP-1β, MCP-1• ↑ IL-12p40 T lymphocytes, monocytes and neutrophils • ↓ Apoptosis B lymphocytes, monocytes and neutrophils • ↓ Capping Rolipram is not yet in the market, but the pharmacokinetics on immune cells have been summarised in table I and of this drug has been studied in healthy volunteers. This represented schematically in figure 1.
drug is rapidly and completely absorbed after an oral doseof 1 mg with a bioavailability of 73%. Plasma levels of the In vitro effects of pentoxifylline
non-metabolised drug decline with a half-life of 2 hours.
Natural killer cell activity. PTX inhibits, in a dose-
Rolipram is rapidly and completely excreted, and the main dependent fashion, the cytotoxic activity of natural killer route of elimination is the urine(20). The reported side-effects cells(21). In addition, a decrease in NK cell activity was of rolipram administration include nausea and emesis.
observed in healthy individuals who received PTX duringa few days as well as in patients with long-lasting PTXtherapy(21). Furthermore, it has been reported that PTX PENTOXIFYLLINE
diminishes natural killer cell-mediated cytotoxicity through Although pentoxifylline has been largely employed as the inhibition of perforin-mediated cell membrane damage(22).
a haemorrheologic agent(19), it is evident that this drug exerts The effect of PTX on NK cells may be important, mainly in many and different effects on immune cells. The those patients that receive it for long periods of time.
antiinflammatory and immunomodulatory actions of PTX Apoptosis. It has been described that PTX has an in vitro
have been studied both in vitro and in vivo, in humans anti-apoptotic effect in two different human cell types, and in animal models of autoimmune diseases. Its effects neutrophils and the U937 monocytic cell line(23). In addition, PHOSPHODIESTERASE INHIBITORS AS IMMUNOMODULATORY DRUGS Cell adhesion and migration. PTX is able to inhibit
the adhesion of human T lymphocytes to the β1 and β2 integrin ligands VCAM-1 and ICAM-1(27). In addition, the Monocyte
by intracellular signals, a phenomenon that is necessary for their ligand interaction, is blocked by this drug. PTX also Pentoxifylline
inhibits the homotypic aggregation of T cells induced by anti-β1 and -β2 integrin chain monoclonal antibodies (mAb).
Furthermore, PTX exerts an inhibitory effect on the polarisation, chemotaxis and transendothelial migration of T lymphocytes Neutrophil
and neutrophils induced by different stimuli(28). It has been also described that PTX reduces the integrin-mediated Endothelial cell
adhesion of lymphocyte activated killer (LAK) cells to fibronectin, endothelium and cultured melanoma andpancreatic tumour cells(29). PTX is also able to inhibit other Figure 1. Schematic representation of the different effects of pentoxifylline
cell-to-cell interactions, including the adhesion of T cells on immune cells. See text for a detailed description of these effects. to keratinocytes(30) as well as the interaction of T lymphocyteswith dermal endothelial cells(31), phenomena in which LFA- PTX is able to reduce the activation-induced apoptosis of 1 and ICAM-1 play an important role. These effects may primed human T lymphocytes(23). Furthermore, it has been contribute to the beneficial effect of this drug in certain reported that this drug significantly attenuates the programmed inflammatory skin diseases. Interestingly, it has been reported cell death of murine pancreatic beta cells induced by interferon- that PTX enhances the impaired chemotaxis of mononuclear gamma (IFN-γ), tumour necrosis factor-α (TNF-α) and nitric leukocytes from patients with vascular and systemic oxide (NO)(24). Therefore, the anti-apoptotic effect of PTX autoimmune diseases(32). These data suggest that PTX exerts may have potential clinical utility. However, the down- a modulatory rather inhibitory effect on leukocyte motility.
regulatory effect of PTX on lymphocyte apoptosis might On the other hand, the effect of this drug on endothelium favour loss of peripheral tolerance or the disregulation of does not seem to be very important. We have found that PTX has a down-regulatory effect on the enhancement of Gene transcription. The expression of c-Rel (a component
expression of ICAM-1 upon the activation of endothelial of NF-κB) induced by anti-CD3 monoclonal antibodies cells with TNF-α(28). However, no significant effect of PTX in T lymphocytes is blocked by PTX, whereas the induction on the expression of E-selectin and VCAM-1 was observed(28). of other NF-κB family members is not significantly Cytoskeleton. It has been described that PTX, at a
affected(25). However, the induction of NF-AT, a transcription concentration of 10 nM, decreases F-actin content in both factor that has similar signalling requirements as c-Rel neutrophils and mononuclear cells(33). This drug also inhibits activation, is not inhibited by PTX. The genes that are concanavalin-induced capping in these cells, as well as the expressed in response to NF-κB include IL-2 and CD25 surface immunoglobulin capping in B lymphocytes(33). These (the IL-2Rα chain). However, PTX only suppresses IL-2 observations suggest that the haemorrheological properties mRNA induction, whereas IL-2Rα chain mRNA levels of PTX may be due to its effects on actin state in the different are not affected by this drug. On the other hand, PTX does not affect the induction of c-Rel in mature B lymphocytes, Lymphocyte activation. PTX has a significant inhibitory
suggesting that this drug exerts a preferential effect on effect on the expression of the lymphocyte activation antigens cell mediated immunity(25). However, PTX seems to have CD25, CD69 and CD98 on the surface of T cells(27). PTX also important effects on B lymphocyte maturation and interferes with early cell activation events such as the differentiation. In this regard, it has been described that elevation of intracellular Ca2+ and the activation of the the activation of the immunoglobulin light chain k gene Na+/H+ cell membrane antiporter induced by PHA and transcription, which occurs during differentiation of pre- phorbol esters, respectively(27). In addition, this drug inhibits B cells to B cells, is inhibited by PTX(26). Furthermore, this the cell cycle progression and cell proliferation of T cells drug reduces the germline transcription of the un-rearranged induced through the CD3/TCR complex(27). Accordingly, k locus, which results in a diminution of the Vk to Jk PTX also inhibits the in vitro generation of cytotoxic T Cytokine synthesis. PTX differentially regulates the
of IL-10 negatively correlated with those of IL-12 p40 production of cytokines depending on the cell type, the subunit(42). On the other hand, it has been reported that stimulus and the PTX concentration employed. At high PTX at 3.5x10–5 M significantly inhibits the production of concentrations, PTX triggers the production of interleukin- TNF-α, IL-2 and IL-4 and that this effect is observed when 6 (IL-6) but not of TNF-α by peripheral blood mononuclear lymphocytes are stimulated with anti-CD3 mAb plus cells. When these cells are stimulated with bacterial phorbol esters, but not with a combination of anti-CD3 and lipopolysaccharides, PTX inhibits the secretion of TNF- anti-CD28 mAbs(43). The effect of PTX on chemokine α as well as the accumulation of TNF-α mRNA, whereas production has also been investigated. PTX is able to inhibit no inhibitory effect is observed on the synthesis of IL-6.
the production of MIP-1α (CCL3), MIP-1β (CCL4) and In contrast, this drug inhibits the secretion of both TNF- MCP-1 (CCL2) by monocytes stimulated with staphylococcal a and IL-6 in T lymphocytes activated with anti-CD3 mAbs(35). Accordingly, Tilg et al. reported that PTX reducesthe expression of TNF-α mRNA, and increases the In vivo effects of Pentoxifylline
production of IL-6, with no effect on the production of The efficacy of PTX as an immunomodulatory and IL-1β in peripheral blood mononuclear cells stimulated antiinflammatory agent has been evaluated in different with phytohemagglutinin(36). In addition, Thanhauser et murine models of disease. The administration of PTX to al. found that PTX exerts an inhibitory effect on the release MLRlpr/lpr mice, which develop an autoimmune disease of interleukin-2 (IL-2), and TNF-α, whereas IL-6 remained similar to human systemic lupus erythematosus (SLE), has unaffected in phytohemagglutinin-stimulated peripheral been shown to diminish the severity of the disease, reducing blood mononuclear cells(37). Interestingly, these in vitro proteinuria and the titre of double-stranded anti-DNA- effects have been corroborated in vivo. When peripheral autoantibodies, and significantly increasing the survival blood mononuclear cells were obtained from healthy rate(45). In a different model of experimental SLE induced volunteers ingesting 5 x 400 mg PTX orally for 2 days, the by injection of human anti-DNA antibodies, the treatment ability of these cells to release TNF-α was significantly with PTX significantly improved the clinical status of mice reduced, while secretion of IL-1β, IL-6 and IL-8 was not by reducing the synthesis of TNF-α and IL-1, the anti-DNA affected(38). In addition, when cells were obtained from levels, and the rate of leukopenia, proteinuria and immune the same individuals 5 days after PTX treatment had been stopped, the release of all four cytokines was significantly Treatment with high doses of PTX can prevent the suppressed. This effect was exerted at the transcriptional concanavalin A-induced hepatitis by suppression of TNF- level, since RNA northern blot analysis revealed reduced α release and inhibition of T cell adhesion to the extracellular cytokine transcripts(38). Furthermore, it has been described matrix(47). In a murine model of allergic pulmonary that the release of the soluble form of TNF receptor p75 inflammation, the administration of PTX during allergen in response to T lymphocyte stimulation with anti-CD3 sensitisation leads to attenuation of airway hyperresponsiveness mAb is reduced by PTX, whereas the release of p55 is not despite the presence of elevated levels of the Th2 cytokine IL-13 and decreased levels of the Th1 cytokine IFN-γ in PTX, at 5x10–4 M, can induce the suppression of synthesis of Th1 cytokines (IL-2 and IFN-γ) both at transcriptional The therapeutic utility of PTX in patients infected with and translational levels, whereas at this concentration this the human immunodeficiency virus has been evaluated.
drug only affects mRNA expression of Th2 cytokines (IL- Patients were asymptomatic, had 300-500 CD4 cells/µl 4 and IL-10)(40). At higher concentrations (10–3 M), PTX is and were not receiving antiretroviral therapy. Treatment able to induce a generalised inhibition of all cytokines(40).
with PTX (1200 mg/day orally) for 4 months induced a On the other hand, Rieckmann et al. reported that PTX transient increase in CD4+ cells in 8 of 9 patients, and CD8+ significantly reduces TNF-α and IL-12 synthesis, but increases cells in 7 of 9 patients(49). This enhancement in cell count IL-4 and IL-10 mRNA expression in mitogen- and antigen- negatively correlated with susceptibility to in vitro mitogen- stimulated lymphocyte cultures as well as in cells from stimulated apoptotic cell death. In addition, this drug patients with multiple sclerosis(41). In an other study, induced an augmentation of IL-2 production stimulated Marcinkiewicz et al. found that PTX inhibits the production by antigen and enhanced lymphocyte proliferation in 8 of of TNF-α, IL-10 and IL-12 p35, whereas it enhances the production of IL-12 p40 by murine peritoneal macrophages(42).
The therapeutic potential of PTX in organ transplantation Accordingly, they observed that the cell culture concentrations has also been explored. A double-blind clinical study PHOSPHODIESTERASE INHIBITORS AS IMMUNOMODULATORY DRUGS TABLE II. Effects of Rolipram
Function
Cell type
• ↓ Expression of CD25, CD69 and CD98• ↓ Cell proliferation• ↓ MAPK (p38) • ↑ Proliferation• ↓ IgE production • ↓ MHC-II expression, ↓ antigen presentation • ↓ Biosynthesis of LTB4, ↓ production of superoxide• ↓ Release of histamine• ↓ [Ca 2+] cytosolic Basophils • ↓ Release of histamine and LTC4 • ↓ Permeability• ↓ Ca2+ mobilization • ↓ Adhesion through β1 and β2 integrins• ↓ Activation of β1 integrins• ↓ Homotypic aggregation induced by β1 integrins• ↓ Polarisation, chemotaxis, extravasation • ↓ Adhesion to endothelial cells• ↓ CD11b/CD18 expression • ↓ CD11b/CD18 expression• ↓ Adhesion to endothelial cells and transendothelial • ↓ NF_B and NFAT activation• ↑ AP-1 and CREB activation • ↓ TNF-α, IL-1β, IL-6, IFN-γ, IL-2, IL-5, IL-4, IL-13 • ↑ IL-10 • ↓ TNF-α, IL-6, MIP-1α, MIP-2, MCP-1 • ↑ Apoptosis (↓ Bcl-2 y Bcl-x; ↑ Bax) comparing PTX versus placebo in patients receiving leprosy reaction, generalised morphea, Schamberg’s disease(58), cadaveric kidney allografts reported reduced plasma TNF- α levels and decreased expression of VCAM-1 in renaltubular endothelium in the PTX group, correlating witha beneficial effect on graft survival(50). PTX and its derivative ROLIPRAM
lisofylline have been reported to induce a reduction in As stated above, rolipram exerts a selective inhibitory toxicity and mortality in patients undergoing bone marrow effect on PDE4, the main PDE subfamily expressed by lymphocytes. In addition, rolipram exhibits a higher potency The anti-inflammatory properties of PTX seem to be than pentoxifylline. By this reason, it has been proposed also beneficial in different skin diseases(53), such as irritant that rolipram and other novel PDE inhibitors are drugs with and contact hypersensitivity reactions(54,55), ulcerating a high therapeutic potential for the treatment of inflammatory necrobiosis lipoidica(56), cutaneous polyarteritis nodosa(57), and immune-mediated diseases. Its effects on immune cells Monocyte
Neutrophil
Rolipram
Basophil
Endothelial cell
Dendritic cell
Eosinophil
Figure 3. Effect of PDE inhibitors on the extravasation of leukocytes towards
an inflammatory foci. The different steps of leukocyte-endothelial cell interaction are indicated as well as the phenomena that are inhibited by pentoxifyllineand rolipram. Figure 2. Schematic representation of the different effects of rolipram on
immune cells. See text for a detailed description of these effects.

stimulated with phytohemagglutinin or anti-CD3 mAb(63).
Cell proliferation responses of human antigen-specific Th1 have been summarised in table II and represented and Th2 lymphocytes are also down-regulated by rolipram(64).
Th2 cell clones seem to be more sensitive than Th1 clonesto PDE4 inhibition, a phenomenon that may be due to the In vitro effects of rolipram
differential expression of PDE4 isoforms in Th1 and Th2 Apoptosis. Rolipram is able to suppress the expression
cells(64). In contrast, rolipram enhances the proliferation of of anti-apoptotic members of the Bcl-2 family (Bcl-2 and B lymphocytes in response to lipopolysaccharides and IL- Bcl-x) and to induce the expression of the pro-apoptotic 4 through a signalling pathway that involves the activity protein Bax, shifting the balance towards a pro-apoptotic of PKA(65). The finding that the PDE3 inhibitor cilostamide direction. Accordingly, rolipram induces the apoptosis in combination with rolipram, markedly suppress the cell mediated by caspases of lymphocytes from patients with proliferation response of lymphocytes to HLA-DR alloantigens B-cell chronic lymphocytic leukemia(60). In addition, rolipram in mixed lymphocyte cultures suggests the potential use of has been shown to exert several important effects on human PDE inhibitors in the prevention of allograft rejection(66).
acute lymphoblastic leukemia cell lines, including suppression As stated above, the non-specific PDE inhibitor pentoxifylline of cell growth, and induction of apoptosis, glucocorticoid has a beneficial effect in patients with kidney allografts and sensitivity, and p53/p21 (WAF1/CIP1) proteins(61).
Leukocyte activation. The role of adenylate cyclase
It has been described that PDE inhibitors affect intracellular activity and PDE has been studied in human T lymphocytes signalling pathways that have a key role in lymphocyte activated with PHA or anti-CD3 plus anti-CD28 mAbs.
activation and function. Matousovic et al. reported that Initially, cAMP levels increase in response to adenylate PDE3 and PDE4 inhibitors are able to block the activation cyclase (< 5 min), and then this elevation is reversed by the of the mitogen activated protein kinase (MAPK) signalling activity of PDE4 (< 2 hr). In the late phase (>2 hr), cAMP pathway, likely by decreasing the activity of Raf-1, due to levels further decrease via PDE1(62). In this work, PDE4 its PKA-catalysed phosphorylation(67). In addition, it has inhibition resulted in reduction of IL-13 synthesis. The role been reported that rolipram inhibits the phosphorylation of PDE4 activity in T cell activation has been tested in of the MAPK p38 in U937 monocytic cells stimulated by additional studies. We have recently found that rolipram IFN-α(68). It is very feasible that rolipram, as pentoxifylline, significantly inhibits the expression of the different lymphocyte has an inhibitory effect on other intracellular signalling activation antigens when T cells are activated with phenomena, including intracellular Ca2+ concentration and phytohemagglutinin (Layseca-Espinosa et al., submitted).
Accordingly, this drug also inhibits the cell proliferation Rolipram is about 40 times more potent that PTX at and the synthesis of IL-2 by CD4+ and CD8+ T lymphocytes suppressing the production of nitric oxide in lipopolysaccharide PHOSPHODIESTERASE INHIBITORS AS IMMUNOMODULATORY DRUGS and IFN-γ stimulated macrophages. This effect occurs in that rolipram is a potent inhibitor of the synthesis of TNF- parallel with an increase in the levels of total cellular cAMP α by activated human monocytes, acting at transcriptional and the inhibition of the inducible nitric oxide synthase at and translational levels(84). Interestingly, this drug is 500 times more potent that the non-specific inhibitor PTX in the The function of antigen presenting cells is also affected reduction of the synthesis of this cytokine(85). As in the case by rolipram. This drug exerts an inhibitory effect on the of PTX, the production of IL-1β and IL-6 is not affected by antigen presentation ability of dendritic cells by decreasing the IC50 of rolipram for the inhibition of TNF-α production(84).
the expression of major histocompatibility complex type However, an additional study reported that rolipram is able II molecules through an IL-10-dependent mechanism(70).
to suppress the production of IL-1β(86). Rolipram is also able Rolipram also blocks the release of TNF-α by dendritic cells to inhibit the production of TNF-α in vivo(84), and an additional in response to lipopolysaccharides(71). The down-modulatory study showed that the treatment with rolipram induces effect of rolipram is also observed on polymorphonuclear an increase in the production of IL-10 with a subsequent leukocytes. This drug inhibits the synthesis of LTC4 induced inhibition of TNF-α and IL-6 release both in endotoxin- by platelet-activating factor and C5a in eosinophils(72) as stimulated macrophages and in endotoxemic mice(87). Rolipram well as the release of histamine and LTC4 from activated enhances IL-10 synthesis and suppresses TNF-α production basophils(73). In neutrophils, rolipram induces the sequestration by a protein kinase A (PKA)-dependent mechanism(88). This of cytosolic Ca2+(74), and inhibits the production of superoxide drug also inhibits the activation of T cells induced by IL-15, as well as the release of elastase(74) and the biosynthesis of resulting in the failure of these cells to induce the production of TNF-α by macrophages(89). It is of interest that rolipram Gene transcription. Specific inhibition of PDE4 affects
exhibits a more potent effect in TNF-α secretion on peripheral the regulation of gene transcription. It has been shown that blood mononuclear cells from atopic patients compared rolipram inhibits NFκB and NFAT activation and stimulates AP-1 and CREB transcription factors in T lymphocytes(76).
The in vitro differentiation of human peripheral blood The down-modulating effect of rolipram on NFκB activation monocytes to macrophages is characterised by profound contributes to the reduction in the synthesis of cytokines changes in the PDE isoenzyme pattern, which is reflected (such as TNF-α) induced by this drug. On the other hand, by an altered susceptibility towards selective PDE inhibitors(91).
the up-regulation of AP-1 and CREB leads to the regulation In monocytes, PDE4-selective inhibitors markedly suppress TNF-α production (80% inhibition), whereas PDE3-specific Cell adhesion and migration. Rolipram attenuates the
compounds exerts a weak effect (10-15% inhibition). The adhesion of neutrophils and eosinophils to activated endothelial combined use of these PDE inhibitors results in an additive cells by inhibiting the expression of the Mac-1 leukocyte effect and a fully abrogation of TNF-α release induced by integrin (CD11b/CD18)(77,78). In addition, this drug inhibits lipopolysaccharides. In contrast, neither PDE3- nor PDE4- the transendothelial migration of eosinophils in vitro(79) as selective drugs markedly affected TNF-α synthesis by well as the migration of these cells induced by antigenic macrophages when used alone (<15%), whereas in combination, challenge in vivo(80). Rolipram also inhibits the adhesion of they led to a maximal inhibition of TNF-α formation by human T lymphocytes to the β1 and β2 integrin ligands VCAM-1 and ICAM-1 (Layseca-Espinosa et al., submitted).
It is also of interest the effect of rolipram on the production This drug also interferes with the activation of β1 integrins of cytokines involved in allergic phenomena. As stated and inhibits the homotypic aggregation of T cells induced above, rolipram is able to inhibit the expression of pro- by anti-β1 and anti-α4 integrin chain mAb (Layseca-Espinosa inflammatory mediators (TNF-α) as well as Th1 (IFN-γ) and et al., submitted). Furthermore, this drug inhibits the Th2 (IL-4 and IL-5) cytokines, at both the mRNA and protein polarisation and transendothelial migration of T lymphocytes levels. Th2 cells are more sensitive to the effect of rolipram induced by the chemokine CXCL12 (SDF-1) and by the compared with Th1 lymphocytes. This may be due, at least chemotactic cytokine IL-15 (Layseca-Espinosa et al., submitted).
in part, to the differential expression of PDE4 isoforms Finally, it has been reported that rolipram inhibits the between these cells. Th1 cells show a reduced gene expression expression of E- and P-selectins, with no effect on the for the PDE4C isoform and a lack of expression for the expression of VCAM-1 and ICAM-1 on the surface of activated PDE4D isoform(63). Rolipram exerts, both in vitro and in vivo, a down-regulatory effect on IL-5 gene expression and protein Cytokine synthesis. As in the case of PTX, rolipram has
production induced by antigen(92). This effect occurs by a an inhibitory effect on TNF-α production. It has been reported cAMP-dependent mechanism that does not involve the activation of PKA(93). Pretreatment of lymphocytes from the activation of CREB that results in an increase of the brain- atopic individuals with rolipram results in marked down- derived neurotrophic factor (BDNF) and trkB mRNA, and regulation of gene expression for IL-4, IL-5(94). In addition, the suppression of the production of pro-inflammatory rolipram inhibits IL-13 gene expression and protein secretion cytokines and other mediators of inflammation(105-107). This in allergen-specific human T lymphocyte clones from asthmatic drug exerts a variety of effects of clinical relevance, such as subjects(95) as well as the PHA-induced IL-13 release from attenuation of endogenous depression and inflammation peripheral blood mononuclear cells from atopic asthma in the central nervous system. The antidepressant properties patients by elevating intracellular cAMP concentrations(96).
of rolipram have been attributed to the increase of synthesis Furthermore, this drug suppresses the release of IL-4 and of BDNF and trkB(105). However, there are some discrepancies IL-13 from antigen-stimulated basophil-enriched leukocyte between in vitro and in vivo effects of rolipram, as well as preparations(97). Rolipram also reduces the IL-4-induced between the results obtained in animal models and in clinical production of IgE in peripheral blood mononuclear cells by interfering with the costimulatory signals provided bymonocytes(98). Finally, rolipram inhibits the secretion of GM- In vivo effects of rolipram
CFS but has no effect on the regulation of chemical mediator The ability of rolipram to down-regulate antigen-driven release by cultured human mast cells(99). All these data T lymphocyte proliferation and to suppress TNF-α production strongly support the therapeutic potential of rolipram in in vitro and in vivo have led to explore its effect in a number of autoimmune disorders including experimental autoimmune Human immunodeficiency virus. In an interesting
encephalomyelitis (EAE) and experimental autoimmune report, Navarro et al. reported that the specific blockade of neuritis (EAN). It has been found that rolipram suppresses PDE4 by rolipram inhibited HIV-1 replication in acutely the production of TNF-α, lymphotoxin-alpha (TNF-β) and infected human T lymphocytes and prevented the depletion IFN-γ by auto-reactive T cells from patients with multiple of CD4+ T cells associated with viral infection(100). This drug sclerosis and rats with EAE(107,108), but has no effect on IL- exerts a direct effect on LTR-dependent transcription, likely 4, IL-10 and TGF-β synthesis(108). Accordingly, rolipram due to the inhibition of NF-κB and NFAT activation.
administration delays and slightly ameliorates the EAE Furthermore, rolipram inhibits the production of cytokines induced by myelin basic protein(109). However, rolipram has involved in the regulation of HIV replication, such as IL-10 no significant effect when it is administered to animals with and TNF-α(100). This effect is exerted on HIV-1-infected human established EAE(109). In vitro experiments suggested that T cells stimulated with anti-CD3 mAbs, with no significant rolipram inhibits the migration of leukocytes into the central effect on lymphocyte proliferation(100). In an additional study, nervous system and, at some extent, down-modulates the rolipram was 10-600 times more potent than PTX in the proliferation of T lymphocytes and activation of macrophages(109). In addition, it has been shown that this Endothelial cells. Blockade of PDE4 activity by rolipram
drug reduces NO production and expression of the inducible inhibits the induction of E-selectin expression on TNF-α- nitric oxide synthase(110). On the other hand, the effect of stimulated human lung microvascular endothelial cells and rolipram has also been investigated in EAN, a CD4+ T cell- interferes with their adhesion to neutrophils(102). In contrast, mediated demyelinating autoimmune disease that is an the combination of PDE3 and PDE4 inhibitors was necessary animal model of Guillain-Barre syndrome. The beneficial to diminish VCAM-1 expression and eosinophil adhesion effect of this drug observed in EAN was associated with to activated endothelium(102). On the other hand, rolipram down-regulation of myelin antigen-induced T lymphocyte reduces the permeability of the endothelial cell monolayer, responses as well as with reduction of IFN-γ, TNF-α, MIP- thus interfering with the extravasation of fluid and leukocytes 1α (CCL3) and MCP-1 (CCL-2) synthesis(111,112). seen in inflammatory conditions(103). In addition, rolipram It has been shown that rolipram exerts a preventive and inhibits the increase in intracellular Ca2+ induced by histamine, therapeutic effect in animal models of collagen-induced thrombin and ATP in human umbilical vein endothelial arthritis(113). Several lines of evidence suggest that the cells, mainly through inhibition of Ca2+ mobilisation from mechanism by which rolipram suppresses arthritis in these models is the reduction of TNF-α and IFN-γ levels in the Central nervous system. PDE4 plays an important role
joints(113). Administration of rolipram to mice with collagen- in the hydrolysis of cAMP in nerve cells. The consequences induced arthritis has a therapeutic effect on both clinical of inhibition of PDE4 by rolipram in these cells include severity and joint bone erosions(114). This drug also abrogates the elevation of synthesis and release of norepinephrine, the formation of edema, and inhibits the cellular influx as PHOSPHODIESTERASE INHIBITORS AS IMMUNOMODULATORY DRUGS well as bone and cartilage destruction(115). In addition, of PTX are necessary to fully exert all its immunomodulatory rolipram exerts an analgesic effect by affecting the nociceptor and anti-inflammatory effects. It is not clear whether or not such concentrations can be reached in vivo, and it is evident Both PTX and rolipram administration to non-obese that it is necessary to develop more specific and potent PDE diabetic mice (an animal model of type 1 insulin-dependent inhibitors. Rolipram and other drugs such as lysofylline are diabetes mellitus) has been shown to reduce the severity of examples of this type of drugs. However, further controlled insulitis and to prevent the development of diabetes(116).
clinical studies are necessary to establish the true role of This drug also has a beneficial effect in other inflammatory these drugs in the therapy of inflammatory and immune- diseases in mice, such as the concanavalin A-induced T cell- mediated conditions. We think that this is a promising area dependent hepatitis(117) and experimental colitis(118). In of pharmacology and immunology research.
addition, it has been reported that rolipram attenuates theenteropathy induced by nonsteroidal anti-inflammatorydrugs, an effect that is independent of the inhibition of TNF- Roberto González-Amaro, M.D., Ph.D.
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