Suppression of human inflammatory cell function by subtype‐selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B

Abstract

1 Of the four major phosphodiesterase 4 (PDE4) subtypes, PDE4A, PDE4B and PDE4D are widely expressed in human in¯ammatory cells, including monocytes and T lymphocytes. We explored the functional role of these subtypes using ten subtype-selective PDE4 inhibitors, each belonging to one of two classes: (i) dual PDE4A/PDE4B inhibitors or (ii) PDE4D inhibitors. 2 These compounds were evaluated for their ability to inhibit antigen-stimulated T-cell proliferation and bacterial lipopolysaccharide (LPS)-stimulated tumour necrosis factor a (TNFa) release from peripheral blood monocytes. 3 All compounds inhibited T-cell proliferation in a concentration-dependent manner; with IC 50 values distributed over an approximately 50 fold range. These compounds also inhibited TNFa release concentration-dependently, with a wider (*1000 fold) range of IC 50 values. 4 In both sets of experiments, mean IC 50 values were signi®cantly correlated with compound potency against the catalytic activity of recombinant human PDE4A or PDE4B when analysed by either linear regression of log IC 50 values or by Spearman's rank-order correlation. The correlation between inhibition of in¯ammatory cell function and inhibition of recombinant PDE4D catalytic activity was not signi®cant in either analysis. 5 These results suggest that PDE4A and/or PDE4B may play the major role in regulating these two in¯ammatory cell functions but do not rule out PDE4D as an important mediator of other activities in mononuclear leukocytes and other immune and in¯ammatory cells. Much more work is needed to establish the functional roles of the PDE4 subtypes across a broader range of cellular functions and cell types.

Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases

“…The different PDE4 subtypes are differently expressed depending on the tissue. PDE4A is expressed in all tissues except in neutrophils (Wang et al 1999), PDE4B is widely expressed and is the pre-dominant PDE4 subtype in monocytes and neutrophils (Wang et al 1999), but lacks in cortex and epithelial cells (Jin et al 1998), PDE4C is absent from circulating inflammatory cells, cortex and hippocampus and has been detected in lung and testis (Obernolte et al 1997, Manning et al 1999, Martin-Chouly et al 2004) and PDE4D is particularly active in lung, cortex, cerebellum and T cells , Jin et al 1998. The up-regulations of the PDE4B subtype in response to pro-inflammatory agents suggest that PDE4B could be particularly involved in inflammatory processes.…”

“…The up-regulations of the PDE4B subtype in response to pro-inflammatory agents suggest that PDE4B could be particularly involved in inflammatory processes. However, by screening a large number of PDE4 inhibitors against the recombinant human enzyme, it has been able to identify a few selective subtype inhibitors (Manning et al 1999). The results obtained using these kinds of compounds suggest that PDE4A and or PDE4B may play the major role in regulating LPS-induced TNF-α release and T-cell proliferation but do not rule out PDE4D as an important mediator of other activities in mononuclear leukocytes and other immune and inflammatory cells (Manning et al 1999.…”

“…However, by screening a large number of PDE4 inhibitors against the recombinant human enzyme, it has been able to identify a few selective subtype inhibitors (Manning et al 1999). The results obtained using these kinds of compounds suggest that PDE4A and or PDE4B may play the major role in regulating LPS-induced TNF-α release and T-cell proliferation but do not rule out PDE4D as an important mediator of other activities in mononuclear leukocytes and other immune and inflammatory cells (Manning et al 1999. Using an in vitro model of DMSO-treated HL60 cells, we found a change of PDE4 subtype profile during differentiation (Jacob et al 2002).…”

T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 and 7A3

“…As a result, there has been considerable interest in the development of specific phosphodiesterase inhibitors for the treatment of inflammatory diseases. To date, most work has centered on PDE4 inhibitors because PDE4 represents a major isozyme in most T cell preparations (16,17). However, in vivo, a major drawback has been the significant side effect of emesis seen with all PDE4 inhibitors tested so far (18).…”

Caboxamycin, a new antibiotic of the benzoxazole family produced by the deep-sea strain Streptomyces sp. NTK 937

“…PDE-4-selective inhibitors have therapeutic potential for treating major diseases, such as asthmatic inflammation and chronic obstructive pulmonary disease 21,22 and several PDE-4 inhibitors have reached the clinical trial of phases II and III status. 22 The PDE-4B enzyme is widely expressed in human inflammatory cells, negatively regulates a wide range of pro-inflammatory and immune cells 21,23 and appears to be involved in the production of the tumor necrosis factor TNF-a and other cytokines promoting the inflammatory response. 22 Therefore, by inhibiting the PDE-4B enzyme, inflammatory response is blocked or strongly reduced.…”