Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1-polarizing capacity.
TL;DR: Findings indicate that PDE4 inhibitors can affect T cell responses by acting at the DC level and may increase the understanding of the therapeutic implication of PDE 4 inhibitors for T(h)1-mediated disorders.
Abstract: Inhibitors of cAMP-specific phosphodiesterase (PDE) 4 have been shown to inhibit inflammatory mediator release and T cell proliferation, and are considered candidate therapies for T(h)1-mediated diseases. However, little is known about how PDE4 inhibitors influence dendritic cells (DC), the cells responsible for the priming of naive T(h) cells. Therefore, we investigated the PDE profile of monocyte-derived DC, and whether PDE4 inhibitors modulate DC cytokine production and T cell-polarizing capacity. We mainly found cAMP-specific PDE4 enzymatic activity in both immature and mature DC. In contrast to monocytes that mainly express PDE4B, we found that PDE4A is the predominant PDE4 subtype present in DC. Immature DC showed reduced ability to produce IL-12p70 and tumor necrosis factor (TNF)-alpha upon lipopolysaccharide or CD40 ligand (CD40L) stimulation in the presence of PDE4 inhibitors, whereas cytokine production upon CD40L stimulation of fully mature DC in the presence of PDE4 inhibitors was not affected. Exposure to PDE4 inhibitors for 2 days during DC maturation did not influence T cell-stimulatory capacity or acquisition of a mature phenotype, but increased the expression of the chemokine receptor CXCR4. Furthermore, DC matured in the presence of PDE4 inhibitors showed reduced capacity to produce IL-12p70 and TNF-alpha upon subsequent CD40L stimulation. Using these PDE4 inhibitor-matured DC to stimulate naive T cells resulted in a reduction of IFN-gamma-producing (T(h)1) cells. These findings indicate that PDE4 inhibitors can affect T cell responses by acting at the DC level and may increase our understanding of the therapeutic implication of PDE4 inhibitors for T(h)1-mediated disorders.
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TL;DR: Apremilast is an orally available targeted PDE4 inhibitor that modulates a wide array of inflammatory mediators involved in psoriasis and psoriatic arthritis, including decreases in the expression of inducible nitric oxide synthase, TNF-α, and interleukin (IL)-23 and increases IL-10.
335 citations
TL;DR: A number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects, including delivery via the inhaled route, and/or development of non‐emetic PDE4 inhibitors and mixed PDE inhibitors.
Abstract: Phosphodiesterase4 inhibitors are currently under development for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease. The rationale for the development of this drug class stems from our understanding of the role of PDE4 in suppressing the function of a range of inflammatory and resident cells thought to contribute toward the pathogenesis of these diseases. Similarly, numerous preclinical in vivo studies have shown that PDE4 inhibitors suppress characteristic features of these diseases, namely, cell recruitment, activation of inflammatory cells and physiological changes in lung function in response to a range of insults to the airways. These potentially beneficial actions of PDE4 inhibitors have been successfully translated in phase II and III clinical trials with roflumilast and cilomilast. However, dose limiting side effects of nausea, diarrhoea and headache have tempered the enthusiasm of this drug class for the treatment of these respiratory diseases. A number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects, including delivery via the inhaled route, and/or development of non-emetic PDE4 inhibitors and mixed PDE inhibitors.
315 citations
Cites background from "Phosphodiesterase 4 inhibitors redu..."
..., 2005) Monocyte B 4A, D 7 Inhibition of TNF-a release (Hatzelmann and Schudt, 2001; Smith et al., 2003; Heystek et al., 2003; Jones et al., 2005) Macrophages A, B, D 1, 3, 7 Inhibition of TNF-a release (Gantner et al....
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..., 2004) DCs A4B, D 1, 3 Inhibition of TNF-a release (Hatzelmann and Schudt, 2001; Heystek et al., 2003) Mast cells Little if any mast cell stabilization (Weston et al....
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TL;DR: Apremilast, given orally at 20 or 30 mg twice daily, seems to be efficacious, safe, and tolerable for patients with moderate to severe plaque psoriasis, and these results support continuing, longer-term studies.
227 citations
TL;DR: An overview of the cyclic AMP axis and its role as a regulator of immune functions is provided and the clinical and translational relevance of interventions with these processes are discussed.
Abstract: Nucleotide signaling molecules contribute to the regulation of cellular pathways. In the immune system, cyclic adenosine monophosphate (cAMP) is well established as a potent regulator of innate and adaptive immune cell functions. Therapeutic strategies to interrupt or enhance cAMP generation or effects have immunoregulatory potential in autoimmune and inflammatory disorders. Here, we provide an overview of the cyclic AMP axis and its role as a regulator of immune functions and discuss the clinical and translational relevance of interventions with these processes.
195 citations
Cites background from "Phosphodiesterase 4 inhibitors redu..."
...Pharmacological inhibition of cyclic nucleotide PDE4, which is highly expressed in DC, for example, suppresses the DC Th1-polarizing capacity (64, 65) and commands secretion of IL-6 and TGF-beta and subsequent induction of Th17 differentiation (66)....
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TL;DR: Various strategies that are currently being pursued to improve efficacy and reduce side-effects of PDE4 inhibitors, including delivery via the inhaled route, mixed PDE inhibitors and/or antisense biologicals targeted towards PDE 4 are discussed.
134 citations
References
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TL;DR: It is shown that neither a Th1- nor a Th2-inducing function is an intrinsic attribute of human myeloid DC, but both depend on environmental instruction and are resistant to further modulation, which may facilitate their potential use in immunotherapy.
Abstract: Dendritic cells (DC) are key initiators of primary immune responses. Myeloid DC can secrete IL-12, a potent Th1-driving factor, and are often viewed as Th1-promoting APC. Here we show that neither a Th1- nor a Th2-inducing function is an intrinsic attribute of human myeloid DC, but both depend on environmental instruction. Uncommitted immature DC require exposure to IFN-gamma, at the moment of induction of their maturation or shortly thereafter, to develop the capacity to produce high levels of IL-12p70 upon subsequent contact with naive Th cells. This effect is specific for IFN-gamma and is not shared by other IL-12-inducing factors. Type 1-polarized effector DC, matured in the presence of IFN-gamma, induce Th1 responses, in contrast to type 2-polarized DC matured in the presence of PGE2 that induce Th2 responses. Type 1-polarized effector DC are resistant to further modulation, which may facilitate their potential use in immunotherapy.
486 citations
Journal Article•
TL;DR: The effects of graded doses of LPS on the cytokine profile, phenotype, and allostimulatory potential of human DC generated by culturing plastic-adherent PBMC in presence of IL-4 and granulocyte-macrophage-CSF are analyzed.
Abstract: To investigate the responses of dendritic cells (DC) during Gram-negative infections, we analyzed the effects of graded doses of LPS on the cytokine profile, phenotype, and allostimulatory potential of human DC generated by culturing plastic-adherent PBMC in presence of IL-4 and granulocyte-macrophage-CSF. First, we found that LPS stimulates the production of high levels of TNF-alpha, IL-6, IL-8, IL-12 by DC and up-regulates their expression of HLA-DR, B7-1, B7-2, and CD40. The effects of LPS were dose dependent, with a significant stimulatory effect already observed at a concentration of 0.1 ng/ml and a plateau being reached at 10 ng/ml. These phenotypic changes correlated with increased allostimulatory properties of LPS-activated DC because DC treated with LPS were significantly more efficient than untreated DC in eliciting IL-2 and IFN-gamma synthesis by alloreactive T cells and stimulating their proliferation. Experiments using neutralizing anti-IL-12 mAb indicated that LPS-induced IL-12 is responsible for the increased production of IFN-gamma but not for the increased proliferation during MLR. Finally, we observed that the DC responses to low levels of LPS (1 ng/ml) were dramatically inhibited by a blocking anti-CD14 mAb, although DC do not express CD14 molecules on their membrane. Experiments using serum depleted of soluble CD14 (sCD14) and sCD14 either purified from human serum or in recombinant form further established that DC respond to LPS via a soluble CD14-dependent pathway.
451 citations
TL;DR: Evidence is presented that beta2-agonists inhibit IL-12 production by both human monocytes in response to lipopolysaccharide (LPS) and dendritic cells stimulated via CD40, which provides new insight into the immunological consequences of the clinical use of beta1-agonists and may suggest new approaches for the treatment of Th1-mediated diseases.
Abstract: Interleukin 12 (IL-12) plays a central role in the immune system by skewing the immune response towards T helper 1 (Th1) type responses which are characterized by high interferon-gamma and low IL-4 production. In this report we present evidence that beta2-agonists inhibit IL-12 production by both human monocytes in response to lipopolysaccharide (LPS) and dendritic cells stimulated via CD40. Inhibition of IL-12 production is selective, as other cytokines produced by monocytes are unaffected. IL-12 inhibition is dependent on beta2-adrenoceptor stimulation and correlates with increased levels of intracellular cAMP. In conjunction with their ability to suppress IL-12 production, when beta2-agonists are added at priming of neonatal T lymphocytes, they inhibit the development of Th1-type cells, while promoting T helper 2 (Th2) cell differentiation. Further, the in vivo administration of a therapeutic dose of salbutamol results in the selective inhibition of IL-12 production by whole blood lymphocytes stimulated in vitro with LPS. These findings provide new insight into the immunological consequences of the clinical use of beta2-agonists and may suggest new approaches for the treatment of Th1-mediated diseases.
451 citations
TL;DR: Multiple forms of cAMP phosphodiesterases, adenylate cyclase and protein kinase A allow cells to tailor the responsiveness of the cAMP-signalling system and to allow for its dynamic adjustment.
445 citations
Journal Article•
TL;DR: In this article, the authors show that PGE2, although it does not induce final dendritic cell maturation by itself, synergizes with IL-1beta and TNF-alpha, and allows their effectiveness at 100-fold lower concentrations.
Abstract: Activation of immature dendritic cells (DC) in peripheral tissues induces their migration to lymph nodes and their maturation into CD83+ DC, which are able to prime naive T cells. The inflammatory cytokines IL-1beta and TNF-alpha induce mature DC, which can secrete IL-12 and promote the development of Th0/Th1-biased cells. DC maturation factors with a Th2-promoting function have not been described. Here we show that PGE2, although it does not induce final DC maturation by itself, synergizes with IL-1beta and TNF-alpha, and allows their effectiveness at 100-fold lower concentrations. While being phenotypically identical with the DC matured in the presence of high concentrations of IL-1beta and TNF-alpha alone, DC matured in the additional presence of PGE2 show impaired IL-12 production and bias naive Th cell development toward the Th2. The ability of DC to produce IL-12 is also suppressed by IL-10, which in contrast to PGE2, inhibits their maturation. The differences in the ability to produce IL-12, established during the final DC maturation, are stable after the removal of modulatory factors. Importantly, fully mature DC become unsusceptible to PGE2 and IL-10. This indicates that the levels of IL-12 production in vivo, in mature DC interacting with Th cells within the lymph nodes, are mainly predetermined at the stage of immature DC in peripheral tissues. These data imply that the character of pathogen-induced local inflammatory reaction can "instruct" local DC to initiate Th1 or Th2-biased responses.
400 citations